Thienycyclohexanone derivatives as ligands of the GABAA α5 receptor subtype

ABSTRACT

A pharamceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is C1-6alkyl, C2-6alkenyl, C2-6-alkynyl, C3-6-cycloalkyl, arylC1-6alkyl, aryl, S(O)pR1.

This application is a 371 of PCT/GB97/02970 Oct. 29, 1997 now WO98/18792 May 7, 1998.

The present invention relates to pharmaceutical compositions comprising substituted thienylcylohexanone derivatives, to their use in therapy and to novel compounds. More particularly, this invention is concerned with substituted derivatives which are ligands for GABA_(A) receptors, in particular for GABA_(A) α5 receptors and are therefore useful in therapy particularly where cognition enhancement is required.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA_(A) receptors which are members of the ligand-gated ion channel superfamily; and (2) GABA_(B) receptors, which maybe members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABA_(A) receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six α subunits, three β subunits, three γ subunits and one δ subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.

Although knowledge of the diversity of the GABA_(A) receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, inside into the extent of subtype diversity is still at an early stage. It has been indicated that an α subunit, a β subunit and a γ subunit constitute the minimum requirement for forming a fully functional GABA_(A) receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a δ subunit also exists, but is apparently uncommon in the native receptor.

Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABA_(A) receptor exists in pentameric form. The selection of at least one α one β and one γ subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit. combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e., there could be 120 possible variants for a receptor composed of five different subunits).

Receptor subtype assemblies which do exist include α1β2γ2, α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ and α4βδ. Subtype assemblies containing an α1 subunit are present in most areas of the brain and account for over 40% of GABA_(A) receptors in the rat. Subtype assemblies containing α2 and α3 subunits respectively account for about 25% and 17% of GABA_(A) receptors in the rat. Subtype assemblies containing an α5 subunit are primarily hippocampal and represent about 4% of receptors in the rat.

A characteristic property of some GABA_(A) receptors is the presence of a number of modulatory sites, of which the most explored is the benzodiazepine (BZ) binding site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABA_(A) receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BA1 subtype has been shown to be pharmacologically equivalent to a GABA_(A) receptor comprising the α1 subunit in combination with β2 and γ2. This is the most abundant GABA_(A) receptor subtype, representing almost half of all GABA_(A) receptors in the brain.

Two other major populations are the α2βγ2 and α3βγ2/3 subtypes. Together these constitute approximately a further 35% of the total GABA_(A) receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain α5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.

It is now believed that agents acting as BZ agonists at α1βγ2, α2βγ2 or α3βγ2 subunits will possess desirable anxiolytic properties. The α1-selective GABA_(A) receptor agonists alpidem and zolpidem are clinically prescribed as hyphotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABA_(A) receptors containing the α1 subunit. Accordingly, it is considered that GABA_(A) receptor agonists which bind more effectively to the α2 and/or α3 subunit than to α1 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at α1 might be employed to reverse sedation or hypnosis caused by α1 agonists.

A number of dementing illnesses such as Alzheimer's disease are characterised by a progressive deterioration in cognition in the sufferer. It would clearly be desirable to enhance cognition in subjects desirous of such treatment, for example for subjects suffering from a dementing illness. It is believed this can be done utilising compounds which are ligands for the GABA_(A) α5 receptor subtype.

WO-A-9616954 mentions three thienylcyclohexanone derivatives substituted by substituted arylaminocarbonyl on the thiophene ring as fungicides.

Van Rhee et al., J. Med. Chem., 1996, 39, 398-406 discloses related compounds as adenosine receptor antagonists which differ in having an ester group on the thiophene ring.

The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

where A is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkylnyl, C₃₋₆cycloalkyl, arylC₁₋₆alkyl, aryl, S(O)_(p)R¹, OR¹ or NR¹R¹⁴;

B is a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatoms is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from: C₁₋₆alkyl; C₁₋₆haloalkyl; halogen; S(O)_(r)R⁴; COR⁵; and aryl or aryl C₁₋₆alkyl wherein the aryl ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano;

R¹ is hydrogen; C₁₋₆-alkyl;, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkenyl each of which is optionally substituted by amino, C₁₋₆-alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl, one, two or three hydroxy groups, one, two or three halogen atoms or a four, five or six-membered saturated heterocyclic ring containing a nitrogen atom and optionally either an oxygen atom or a further nitrogen atom which ring is optionally substituted by C₁₋₄alkyl on the further nitrogen atom, aryl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro, cyano, C₁₋₆alkylcarbonylamino, hydroxy or C₁₋₆alkoxy; or a five-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by halogen, C₁₋₆alkoxy, C₁₋₆alkylthio, aryl C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl;

R² and R³ are independently hydrogen or C₁₋₆alkyl or together with the carbon atom to which they are attached form a C₃₋₈ cycloalkyl group;

R⁴ is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl or CH₂(CO)_(m)NR⁸R⁹;

R⁵ is NR⁶R⁷, C₁₋₆alkyl or C₁₋₆alkoxy;

R⁶ is independently as defined for R⁴;

R⁷ is aryl optionally substituted by halogen, nitro or cyano;

R⁸ is hydrogen C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₂₋₆alkenyl, C₂₋₆alkynyl; arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro or cyano; thiophene or pyridine;

R⁹ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano;

R¹⁰ is hydrogen, hydroxy, C₁₋₆alkoxy, C₂₋₆alkenyloxy or C₂₋₆alkynyloxy;

R¹¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₂₋₆haloalkenyl or C₂₋₆haloalkynyl;

R¹² and R¹³ are individually hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₃₋₈cycloalkyl or R¹² and R¹³, together with the nitrogen atom to which they are attached, form a saturated 4 to 8 membered ring optionally containing an oxygen atom or a further nitrogen atom as a ring member, the further nitrogen atom being unsubstituted or substituted by C₁₋₄alkyl, C₂₋₄alkenyl or C₂₋₄alkynyl;

R¹⁴ is hydrogen or C₁₋₆alkyl;

L is a bond or an unbranched, saturated or monounsaturated hydrocarbon chain having 1-6 carbon atoms;

m is zero or 1;

n is 1 or 2;

p is zero, 1 or 2;

q is 1 or 2; and

r is 0, 1 or 2;

and a pharmaceutically acceptable excipient.

B is preferably a 5- or 6-membered optionally substituted aromatic ring.

Thus when B is an aromatic ring it may be a thiazole, pyrazole, pyrimidine, tetrazole, triazole, oxadiazole, oxazole, pyridine, imidazole or pyrazine which is unsubstituted or substituted by C₁₋₆alkyl, halogen, SR⁴, COR⁵ or benzyl optionally substituted by halogen. When B is a 5- and 6-membered ring having one unsaturation it is preferably oxazolidinyl or imidazolyinyl optionally substituted by halogen or C₁₋₄alkyl.

Particularly embodiments of B are (1-phenylsulphonyl)pyrazol-3-yl, 1-acetylpyrazol-3-yl, (3-ethoxycarbonyl)isoxazol-5-yl, (3-isopropyl)-1,2,4-oxaidazol-5-yl, imidazolin-2-yl, pyrazol-4-yl, 2-methyl-1,3,4-oxadiazol-5-yl, oxazolidin-2-yl, 2-methyltetrazol-5-yl, pyrazol-3-yl, 2-propyltetrazol-5-yl, thiazol-2-yl, 4-methyl-1,2,4-triazol-3-yl, (4-ethoxycarbonyl)thiazol-2-yl, (4-trifluoromethyl)thiazol-2-yl, (4-acetyl)thiazol-2-yl, (4-methyl)thiazol-2-yl, pyrrol-2-yl, pyrid-2-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-benzyl-1,2,4-triazol-3-yl, 1-methyl-1,2,4-triazol-3-yl, oxazol-2-yl, pyrazin-2-yl, pyrimidin-5-yl, 3-(N-methylaminocarbonyl)thiazol-2-yl, thiazol-5-yl, isoxazol-5-yl, pyrid-3-yl, pyrid-4-yl, 1,3,4-oxadiazol-5-yl and 1-methylsulphonylpyrazol-3-yl.

R¹ is preferably C₁₋₆alkyl, C₂₋₆alkenyl or C₃₋₆cycloalkyl each of which is optionally substituted by amino, di(C₁₋₆alkyl)amino, hydroxy, C₁₋₆alkoxy C₁₋₆alkylaminocarbonyl or one, two or three halogen atoms; aryl or arylC₁₋₆alkyl optionally substituted on the aryl ring by halogen, C₁₋₆alkylcarbonylamino or C₁₋₆alkoxy; or a five-membered aromatic ring containing 1, 2 or 3 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered aromatic ring containing 1 or 2 nitrogen atoms, which ring is optionally substituted by halogen, C₁₋₆alkoxy, C₁₋₆alkylthio, aryl or C₁₋₆alkyl.

More preferably R¹ is C₁₋₆alkyl, C₁₋₄alkenyl, or C₄₋₆cycloalkyl each of which is optionally substituted by di(C₁₋₄alkylamino, C₁₋₄alkoxy, C₁₋₄alkylaminocarbonyl, one or two hydroxy groups or three fluorine atoms; phenyl or phenylC₁₋₄alkyl optionally substituted on the phenyl ring by chlorine, fluorine, C₁₋₄alkoxy or C₁₋₄alkylcarbonylamino; or a pyridine, thiophene, furan, pyrimidine, thiazole, imidazole, triazole or thiadiazole, each of which is unsubstituted or substituted by C₁₋₄alkyl, phenyl, fluorine or C₁₋₄alkylthio.

When A is not S(O)_(p)R¹, OR¹ or NR¹R¹⁴ it is preferably C₁₋₆alkyl, C₂₋₆-alkenyl or C₃₋₆cycloalkyl.

When A is OR¹, R¹ is generally C₁₋₆alkyl optionally substituted by C₁₋₄alkoxy, C₃₋₆cycloalkyl or aryl.

Particularly embodiments of A are phenyl, cyclohexyl, 2-methylprop-1-enyl, methylthio, ethyl, isopropyl, propyl, cyclobutyl, but-3-enyl, cyclopropyl, methanesulphonyl, methyl, henzyl, methanesulphinyl, (1,1-dimethylethyl)thio, pentylthio, (4-methyl-1,2,4-triazol-3-yl)thio, hexylthio, benzylamino, (3-imidazol-1-ylpropyl)amino, (pyrid-2-yl)amino, 2-methylprop-1-yl, [3-(4-methylpiperazin-1-yl)propyl]amino, methylamino, (2-hydroxyethyl)amino, azetidin-1-yl, tert-butylamino, isopropylthio, (2-hydroxyethyl)thio, methoxy, dimethylamino, cyclobutoxy, phenoxy, butylthio, (3-chloropropyl)thio, (2-phenylethyl)thio, propylthio, (2-methylbutyl)thio, (2,2,2-trifluoroethyl)thio, (1-methylpropyl)thio, (4-chlorophenyl)thio, (3-fluorophenyl)thio, (4-acetylaminophenyl)thio, (4-methoxyphenyl)thio, (1-methylimidazol-2-yl)thio, (thiophen-2-yl)thio, (imidazol-2-yl)thio, (4-phenylthiazol-2-yl)thio, (1,2,4-triazol-3-yl)thio, (5-methyl-1,3,4-thiadiazol-2-yl)thio, (5-methylthio-1,3,4-thiadiazol-2-yl)thio, benzylthio, cyclopentylthio, (2-methylpropylthio, (furan-2-ylmethyl)thio, (2-hydroxy-1-methylpropyl)thio (2,3-dihydroxypropyl)thio, (2-hydroxypropyl)thio, ((N-methylaminocarbonyl)methyl)thio, (pyrid-4-yl)thio, (pyrimidin-2-yl)thio, (thiazol-2-yl)thio, prop-2-enylthio, (pyrid-2-yl)thio, ethylthio, phenylthio, (N,N-dimethyl-2-aminoethyl)thio, (2-methoxyethyl)thio, (furan-2-ylmethyl)amino, (2-methylpropyl)amino, propylamino, (2-methoxyethyl)amino, cyclopropylamino, isopropylamino, ethylamino cyclobutylamino and isopropoxy.

R² and R³ are preferably independently chosen from hydrogen and methyl or are attached to the same carbon atom and together with that atom form a C₃₋₆cycloalkyl group, and are most preferably both methyl. Preferably R² and R³ are geminal to each other, preferably at the 6-position, i.e. beta to the carbonyl group in formula I.

R⁴ may be hydrogen, C₁₋₄alkyl, C₂₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, aryl or CH₂(CO)_(m)NR⁸R⁹, R⁴ is preferably hydrogen, C₁₋₄alkyl or CH₂(CO)_(m)NR⁸R⁹, more preferably hydrogen, methyl or CH₂CONR⁸R⁹ and most preferably methyl or CH₂CONR⁸R⁹.

R⁵ is preferably methyl, ethoxy, ethoxy or NR⁶R⁷ and most preferably methyl, ethoxy or NR⁶R⁷.

R⁶ may be hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, aryl or CH₂(CO)_(m)NR⁸R⁹. R⁶ is preferably hydrogen or C₁₋₄alkyl and most preferably hydrogen.

R⁷ is preferably phenyl unsubstituted or substituted by halogen, nitro or cyano, more preferably optionally substituted by halogen, such as chlorine.

R⁸ is preferably hydrogen or C₁₋₆alkyl and most preferably hydrogen.

R⁹ is preferably C₁₋₆alkyl or phenyl unsubstituted or substituted by one, two or three substituents independently chosen from halogen, nitro and cyano, more preferably C₁₋₆alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen and nitro and most preferably tert-butyl or phenyl optionally substituted with one or two substituents chosen from chlorine and nitro, such as 4-chlorophenyl.

R¹⁰ is generally hydrogen, hydroxy or C₁₋₄alkoxy and most preferably hydrogen.

R¹¹ is generally C₁₋₄alkyl or C₁₋₄haloalkyl, more particularly C₁₋₁alkyl or C₁₋₄fluoroalkyl, and most preferably CF₃.

R¹² and R¹³ are preferably independently hydrogen, C₁₋₄alkyl or C₃₋₆cycloalkyl or R¹² and R¹³, together with the nitrogen atom to which they are attached, form a saturated 5 to 7-membered ring optionally containing an oxygen atom or a further nitrogen atom at the 4-position the further nitrogen atom being unsubstituted or substituted with C₁₋₄alkyl. More particularly R¹² and R¹³ are independently hydrogen, methyl or cyclohexyl or R¹² and R¹³ together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine ring the further nitrogen atom in the piperazine ring being optionally substituted by methyl.

R¹⁴ is generally hydrogen or C₁₋₄alkyl and most preferably hydrogen.

L is preferably a bond or an unbranched unsaturated hydrocarbon chain having 1 to 4 carbon atoms, more particularly L is a bond or —CH═CH—. Generally L is a bond.

m is preferably 1.

n is preferably 1.

p is preferably zero or two, most preferably zero.

q is preferably 1.

r is preferably 1.

A subclass of compositions according to the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in which:

A is SR¹;

B is a nitrogen containing aromatic ring which is 5-membered and contains 1, 2, 3, or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or is 6-membered and contains 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by C₁₋₆alkyl, halogen, SR⁴, COR⁵ or benzyl optionally substituted by one or two substituents independently chosen from halogen, nitro and cyano;

R¹ is C₁₋₆alkyl, C₁₋₄alkenyl, or C₃₋₆cycloalkyl each of which is optionally substituted by di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylaminocarbonyl, one or two hydroxy groups or three fluorine atoms; phenyl or phenylC₁₋₄alkyl optionally substituted on the phenyl ring by chlorine, fluorine, C₁₋₄alkoxy or C₁₋₄alkylcarbonylamino; or a pyridine, thiophene, furan, pyrimidine, thiazole, imidazole, triazole or thiodiazole, each of which is unsubstituted or substituted by C₁₋₄alkyl, phenyl, fluorine or C₁₋₄alkylthio;

R² and R³ are independently chosen from hydrogen and methyl;

R⁴ is hydrogen, methyl or CH₂CONR⁸R⁹;

R⁵ is methyl, methoxy, ethoxy or NR⁶R⁷;

R⁶ is hydrogen or C₁₋₄alkyl;

R⁷ is phenyl unsubstituted or substituted by halogen, nitro or cyano;

R⁸ is hydrogen or C₁₋₆alkyl;

R⁹ is C₁₋₆alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen or nitro;

R¹⁰ is hydrogen;

R¹¹ is C₁₋₄alkyl or C₁₋₄fluoroalkyl;

R¹² and R¹³ are independently hydrogen, methyl or cyclohexyl or R¹² and R¹³ together with the nitrogen atom to which they are attached form a piperidine, piperazine or morpholine ring, the further nitrogen atom in the piperazine ring being optionally substituted by methyl;

R¹⁴ is hydrogen or C₁₋₄alkyl;

L is a bond or —CH═CH—;

p is zero; and

q is 1;

and a pharmaceutically acceptable excipient.

The preferred definitions of each substituent hereinbefore recited apply mutotis mutandis to this subclass.

The present invention also provides pharmaceutical composition comprising a compound of formula (I′) or a pharmaceutically acceptable salt thereof:

where Het is a 5-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from C₁₋₆alkyl; halogen; SR^(4′); COR^(5′); and phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano,

R^(1′) is hydrogen, C₁₋₆-alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkynyl C₂₋₆alkenyl, C₂₋₆alkynyl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro or cyano; thiophene or pyridine;

R^(2′) and R^(3′) are independently hydrogen or C₁₋₆alkyl;

R^(4′) is C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkylnyl or CH₂(CO)_(m)-NR^(5′)R^(9′);

R^(5′) is NR^(6′)R^(7′), C₁₋₆alkyl or C₁₋₆alkoxy;

R^(6′) is hydrogen or is independently as defined for R^(4′) ;

R^(7′) is aryl optionally substituted by halogen, nitro or cyano;

R^(8′) is independently as defined for R^(1′);

R^(9′) is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano;

m′ is zero or 1; and

p′ is zero, 1 or 2;

and a pharmaceutically acceptable excipient.

R^(1′) is preferably C₁₋₆alkyl, arylC₁₋₆alkyl wherein the aryl ring is unsubstituted or substituted by halogen, nitro or cyano, thiophene or pyridine; more preferably C₁₋₆alkyl, phenylC₁₋₆alkyl optionally substituted on the phenyl ring by halogen, nitro or cyano, thiophene or pyridine; more preferably still C₁₋₆alkyl and most preferably methyl.

R^(2′) and R^(3′) are preferably independently chosen from hydrogen and methyl and are most preferably both methyl. Preferably R^(2′) and R^(4′) are geminal to each other, preferably at the 6-position.

R^(4′) is preferably hydrogen, C₁₋₄alkyl or CH₂(CO)_(m)—NR^(8′)R^(9′), more preferably hydrogen, methyl or CH₂CONR^(8′)R^(9′) and most preferably hydrogen or methyl.

R^(5′) is preferably methyl, methoxy or NR^(6′)R^(7′) and most preferably methyl or NR^(6′)R^(7′).

R^(6′) is preferably hydrogen or C₁₋₄alkyl and most preferably hydrogen.

R^(7′) is preferably phenyl unsubstituted or substituted by halogen, nitro or cyano, more preferably optionally substituted by halogen, such as chlorine.

R^(8′) is preferably hydrogen or C₁₋₆alkyl and most preferably hydrogen.

R^(9′) is preferably C₁₋₆alkyl or phenyl unsubstituted or substituted by one, two or three substituents independently chosen from halogen, nitro and cyano, more preferably C₁₋₆alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen and nitro and most preferably tert-butyl or phenyl optionally substituted with one or two substituents chosen from chlorine and nitro, such as 4-chlorophenyl.

m′ is preferably 1.

p′ is preferably zero.

Het is preferably a nitrogen containing ring such as a pyrimidine or pyrazole. Het may be unsubstituted. Het may be substituted. When Het is a pyrimidine it is preferably attached to the rest of the compound via the 4-position and when a pyrazole via the 3-position. When Het is a pyrimidine it is preferably optionally substituted at the 2-position and when a pyrazole at 1- or 4-position.

Het is preferably unsubstituted or substituted by one substituent. When Het is a pyrimidine it is preferably optionally substituted by a group SR^(4′) where R^(4′) is as defined in any of the definitions of R^(4′) above. When Het is a pyrazole it is preferably optionally substituted at the 4-position by a halogen such as bromine or by a group COR⁵′ where R⁵′ is as defined above. Het is optionally not a thiazole.

A subclass of compositions according to the present invention comprises a compound of formula (I′) in which:

Het is a nitrogen containing aromatic ring which is 5-membered and contains 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or is 6-membered and contains 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by C₁₋₆alkyl, halogen, SR⁴′, COR⁵′ or phenyl optionally substituted by one or two substituents independently chosen from halogen, nitro and cyano;

R¹′ is C₁₋₆alkyl, arylC₁₋₆alkyl, thiophene or pyridine;

R²′ and R³′ are independently chosen from hydrogen and methyl;

p′ is zero; and

R⁴′, R⁵′, R⁶′, R⁷′, R⁸′, R⁹′ and m′ are as defined for formula (I′);

and a pharmaceutically acceptable excipient.

An alternative subclass of compositions according to the present invention comprises a compound of formula (I′) in which:

Het is a nitrogen containing aromatic ring which is 5-membered and contains 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or is 6-membered and contains 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by halogen, SR⁴′ or COR⁵′;

R¹′ is C₁₋₆alkyl, arylC₁₋₆alkyl, thiophene or pyridine;

R²′ and R³′ are independently chosen from hydrogen and methyl;

R⁴′ is hydrogen or C₁₋₄alkyl;

p′ is zero; and

R⁵′, R⁶′, R⁷′, R⁸′, R⁹′ and m′ are as defined for formula (I′); and a pharmaceutically acceptable excipient.

The preferred definitions of each substituent hereinbefore recited for compound of formula (I′) apply mutatis mutandis to both these subclasses.

Specific Examples of compounds which can be used in the compositions of the present invention are:

6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-(1-[4-(chlorophenyl)aminocarbonyl]pyrazol-3-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-(4-bromopyrazol-3-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-dimethyl-3-methylthio-1-(2-methylthiopyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-dimethyl-3-methylthio-1-(2-thiopyrimidin-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-dimethyl-3-methylthio-1-[1-(phenylaminocarbonyl)pyrazol-3-yl]-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-(1-acetylpyrazol-3-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-[2-([2-chlorophenyl]aminocarbonylmethylthio)pyrimidin-4-yl]-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-dimethyl-1-(1-methylpyrazol-3yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one.

The pharmaceutically acceptable salts of the above compounds can also be used in the compositions of the present invention.

Further specific compounds which can be used in the compositions of the present invention are:

6,6-Dimethyl-1-(2-methyltetrazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-ethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(2-propyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]-thiophen-4-one;

6,6-Dimethyl-1-(1-methanesulphonylpyrazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-(2-methylprop-1-yl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-propyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-phenyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Cyclohexyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

3-Cyclobutyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-(But-3-enyl)-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3Cyclopropyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-(2-methylprop-1-enyl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-thione;

3-Methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydro[c]thiophen-4-one;

6,6-Dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-(Thiazol-2-yl)-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Benzyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-((1-phenylsulphonyl)pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropylthio-1-(2-methyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-(1-Acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-[(1,1-dimethylethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(4-methyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-((4-trifluoromethyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-dimethylamino-1-((4-ethoxycarbonyl)thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

1-((4-Acetyl)thiazol-2-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-((4-methyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-hydroxyethyl)thio)-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Methylthio-1-(thiazol-2-yl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene;

6,6-Dimethyl-3-methylthio-1-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(4-benzyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(1-methyl-1,2,4-triazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(oxazolidin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Methylthio-1-(oxazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(pyrazin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(imidazolin-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Methylthio-6,6-spirocyclohexyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(3-(N-methylaminocarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(thiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-tert-butylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Cyclobutoxy-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-[(3-ethoxycarbonyl)isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-phenoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-pentylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Butylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-[(3-Chloropropyl)thio]-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-phenylethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-propylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-methylbutyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((2,2,2-trifluoroethyl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-((4-Chlorophenyl)thio)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((3-fluorophenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-((4-Acetylaminophenyl)thio)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((4-methoxyphenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((1-methylimidazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((thiophen-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((imidazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((4-phenylthiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((1,2,4-triazol-3-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((5-methyl-1,3,4-thiadiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((4-methyl-1,2,4-triazol-3-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((5-methylthio-1,3,4-thiadiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Benzylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Cyclopentylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-hexylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((furan-2-ylmethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-hydroxy-1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2,3-dihydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-hydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-(((N-methylaminocarbonyl)methyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-4-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrimidin-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((thiazol-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-(prop-2-enylthio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-ethylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-phenylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((N,N-dimethyl-2-aminoethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-[(2-hydroxypropyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-[(2-methoxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-1-(isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

7,7-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-(Benzylamino)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((furan-2-ylmethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-methylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-(propylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((3-imidazol-1-ylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-methoxyethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Cyclopropylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((pyrid-2-yl)methylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-([3-(4-methylpiperazin-1-yl)propyl]amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-ethylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-((2-hydroxyethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Cyclobutylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-(Azetidin-1-yl)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-isopropoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Methylthio-1-(pyrid-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

3-Methylthio-1-(pyrid-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

6,6-Dimethyl-3-methylthio-1-(2-methyl-1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; or

6,6-Dimethyl-3-methylthio-1-(1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one;

and the pharmaceutically acceptable salts thereof.

Preferably the compositions according to the present invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, by inhalation or insufflation or administration by trans-dermal patches or by buccal cavity absorption wafers.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably. sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

Compositions of the present invention may also be presented for administration in the form of trans-dermal patches using conventional technology. The compositions may also be administered via the buccal cavity using, for example, absorption wafers.

In disorders associated with GABA_(A) α receptors, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The present invention also provides a process for the preparation of a pharmaceutical composition which comprises adding a compound of formula (I) or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable excipient.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body, in particular for the treatment or prevention of conditions for which the administration of a cognition enhancing agent is desirable, such as Alzheimer's disease.

The compounds of formula (I) are of potential value in the treatment or prevention of a wide variety of clinical conditions which can be alleviated by a ligand selective for GABA_(A) receptors containing the α5 subunit. In particular, they are desirably inverse agonists of the α5 subunit.

Thus, for example, such a ligand can be used in a variety of disorders of the central nervous system. Such disorders include delirium, dementia and amnestic and other cognitive disorders. Examples of delirium are delirium due to substance intoxication or substance withdrawal delirium due to multiple etiologies and delirium NOS (not otherwise specified). Examples of dementia are: dementia of the Alzheimer's type with early onset which can be uncomplicated or with delirium, delusions or depressed mood; dementia of the Alzheimer's type, with late onset, which can be uncomplicated or with delirium delusions or depressed mood; vascular dementia which can be uncomplicated or with delirium, delusions or depressed mood; dementia due to HIV disease; dementia due to head trauma; dementia due to Parkinson's disease; dementia due to Huntington's disease; dementia due to Pick's disease; dementia due to Creutzfeld-Jakob disease; dementia which is substance-induced persisting or due to multiple etiologies; and dementia NOS. Examples of amnestic disorders are amnestic disorder due to a particular medical condition or which is substance-induced persisting or which is amnestic disorder NOS. In particular the compounds of formula (I) may be of use in conditions which require cognition enhancement.

Where the compounds of the present invention are selective ligands for GABA_(A) α2 or α3 subtype receptors they may be used in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; and depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder bipolar I and bipolar II manic disorders, and cyclothymic disorder.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a condition requiring the administration of a ligand selective for GABA_(A) receptors containing the α5 subunit, in particular for conditions requiring cognition enhancement such as Alzheimer's disease.

There is also disclosed a method of treatment or prevention of a condition associated with GABA_(A) receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically or prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In particular there is disclosed the treatment and prevention of conditions which require the administration of a cognition enhancing agent, such as Alzheimer's disease.

As used herein, the expression “C₁₋₆alkyl” includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl. isopropyl and t-butyl. Derived expressions such as “C₂₋₆alkenyl”, “C₂₋₆alkynl”, “C₁₋₄alkyl”, “C₂₋₄alkenyl” and “C₂₋₄alkynyl” are to be construed in an analogous manner.

The expression “C₃₋₆cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. “C₅₋₆cycloalkenyl”, “C₃₋₈cycloalkyl” and “C₅₋₇cycloalkyl” are to be construed analogously.

Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, tetrazolyl, oxadiazolyl and thiadiazolyl groups. These rings also include thiazolyl and triazolyl groups.

The term “halogen” as used herein includes fluorine, chlorine, bromine and iodine especially fluorine, chlorine and bromine.

The expression “arylC₁₋₆alkyl” as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl. “ArylC₂₋₆alkenyl” and “arylC₂₋₆alkynyl” should be construed in an analogous fashion.

Typical aryl groups include phenyl and naphthyl. Preferably the aryl is phenyl.

For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

Where the compounds of formula (I) have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of formula (I) possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

The present invention also provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above. The skilled person will appreciate that the alternative and preferred embodiments of these compounds in the pharmaceutical compositions described above are also alternative and preferred embodiments of the novel compounds of formula (I) provided by the present invention.

Aptly novel compounds of this invention include those wherein R² and R³ are not 6-position gem-dimethyl.

Aptly novel compounds of this invention include those wherein p is 1 or 2.

Aptly novel compounds of this invention include those wherein Her is not a thiazole, pyrimidine or pyrazole.

Aptly novel compounds of this invention include those wherein R¹ is not methyl.

Aptly novel compounds of this invention include those wherein R⁴ is not hydrogen, methyl or CH₂(CO)_(m)NR⁸R⁹.

The present invention also provides a process for producing a compound of formula (I) which comprises:

(i) reacting a compound of formula II:

in which R², R³ are as defined above, with NaH, then with CS₂, then with a compound of formula III and then with a compound of formula IV:

HalR¹  (III)

Hal′CH₂R¹⁵  (IV)

in which R¹ is as defined above, Hal is a halogen atom such as iodine, Hal′ is a halogen atom such as bromine or chlorine and R¹⁵ is CN, COH C(O)C₁₋₆alkyl or CO₂C₁₋₆alkyl to produce a compound of formula VI:

in which A is S(O)_(p)R¹, p is zero and R¹.R².R¹⁵ and q are as defined above and when R¹⁵ is CO₂C₁₋₆alkyl optionally converting it by hydrolysis to a group of formula C0 ₂H and optionally decarboxylating this group to leave a hydrogen atom and optionally converting the hydrogen to a bromine atom by reacting with a brominating agent such as N-bromo succinimide or copper (I) bromide; and

(ii) converting the group R¹⁵ to a group B as defined above by standard techniques to obtain a compound of formula I;

(iii) optionally oxidising the compound of formula VI or the compound of formula I thus obtained to a compound of formula VI or I in which p is 1 or 2, for example by using a stoichiometric quantity of mCPBA, generally in a solvent such as CH₂Cl₂:dioxan with cooling to about −78° C.; and

(iv) optionally converting the compound of formula VI or I, as the case may be, to a compound of formula VI or I in which A is other than S(O)_(p)R¹ by standard techniques.

Step (i) of the above process constitutes a further feature of the present invention. It is generally carried out in a solvent such as DMF and at about 0° C. to about room temperature.

Illustrative examples of conversions of the group R¹⁵ to a group B are as follows; the skilled worker would have no difficulty in adapting these methods or in using other standard techniques to produce compounds in which B is other than as illustrated here:

when R¹⁵ is CN it can be converted to: a tetrazole using, for example, sodium azide, a thiazole using H₂S and HC(O)CH₂Cl: and a triazole using formyl hydrazine;

when R¹⁵ is C0 ₂H it can be converted to an oxadiazole by using: carbonyldiimidazole and an amide oxime; or hydrazine and formic acid:

when R¹⁵ is C(O)CH₃ it can be converted to an isoxazole using EtOC(O)H and NH₂OH.HCl.

Alternatively the group B can replace the group R¹⁵ when the latter is bromine by a Stille reaction using the appropriate trialkyltin derivative and a catalyst such as dichlorobis(triphenylphosphine)palladium (II) or palladium tetrakisphenylphosphine or by a Suzuki reaction using the appropriate boronic acid derivative.

Further details of the above reactions can be found, for example, in Comprehensive Organic Syntheses, ed. B. M. Trost. Pergamon Press, Oxford.

Compounds of formula I or VI in which A is SR¹ can be obtained by reacting a compound of formula I or VI in which A is S(O)_(p)R¹ where p is one or two and R¹ is as defined above with a thiol in the presence of a base.

Compounds of formula I or VI in which A is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₃₋₆cycloalkyl can be obtained by reacting a compound of formula I or VI in which A is S(O)_(p)R where p is zero or two with an appropriate Grignard reagent.

Compounds of formula I or VI in which A is OR¹ can be obtained by reacting a compound of formula I or VI in which A is S(O)_(p)R¹ and p is one or two with an alcohol in the presence of a strong base.

Compounds of formula I or VI in which A is NR¹R¹⁴ can be obtained by reacting a compound of formula I or VI in which A is S(0)_(p)R¹ and p is one or two with an amine.

It will be understood that the above transformations of S(O)_(p)R¹ are illustrative and other standard techniques known to the skilled person may alternatively be used. The above reactions are illustrated in the Examples.

Compounds of formula VI in which R¹⁵ is CN, Br or C(O)CH₃, p is zero, R¹ is CH₃ and R² and R³ are 6,6-dimethyl are commercially available.

The compound of formula VI in which p is zero, R¹ is CH₃, R² and R³ are 6,6-dimethyl and R¹⁵ is bromo can be prepared from

which is commercially available by heating the above compound with 1M HCl in THF and methanol.

The compound of formula I in which A is methylthio, B is pyrazol-3-yl, R² and R³ are 6,6-dimethyl and q is 1 is commercially available; it can also be made by the methods disclosed herein.

Compounds of formulae (II), (III) and (IV) are known in the art or can be made by known methods from known starting materials.

The following Examples illustrate pharmaceutical compositions according to the invention.

COMPOSITION EXAMPLE 1A Tablets Containing 1-25 MG of Compound

Amount mg Active Ingredients(s) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 20.0 20.0 Modified food corn starch 20.0 20.0 20.0 Lactose 58.5 57.5 34.5 Magnesium Stearate 0.5 0.5 0.5

COMPOSITION EXAMPLE 1B Tablets Containing 26-100 MG of Compound

Amount mg Active Ingredients(s) 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Magnesium Stearate 0.5 0.5 0.5

The active ingredient(s), cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.0 mg, 2.0 mg. 25.0 mg, 26.0 mg, 50.0 mg and 100 mg of the active compound per tablet.

COMPOSITION EXAMPLE 2 Parenteral Injection

Amount Active Ingredient(s) 1 to 100 mg Citric Acid Monohydrate 0.75 mg Sodium Phosphate 4.5 mg Sodium Chloride 9 mg Water for injection to 10 ml

The sodium phosphate, ditric acid monohydrate and sodium chloride are dissolved in a portion of the water. The active ingredient(s) is (are) dissolved or suspended in the solution and made up to volume.

COMPOSITION EXAMPLE 3 Topical Formulation

Amount Active Ingredient(s) 1-10 g Emulsifying Wax 30 g Liquid paraffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient(s) is (are) is added and stirring continued until dispersed. The mixture is then cooled until solid.

The following Examples illustrate the compounds of the present invention.

The compounds in accordance with this invention potently inhibit the binding of [³H]-flumazenil to the benzodiazepine binding site of human GABA_(A) receptors containing the α5 subunit stably expressed in Ltk cells.

Reagents

Phosphate buffered saline (PBS).

Assay buffer: 10 mM KH₂PO₄, 100 mM KCl, pH 7.4 at room temperature.

[³H]-Flumazenil (18 nM for α1β3λ2 cells; 18 nM for α2β3λ2 cells; 10 nM for α3β3λ2 cells; 10 nM for α5β3λ2 cells) in assay buffer.

Flunitrazepam 100 μM in assay buffer.

Cells resuspended in assay buffer (1 tray to 10 ml).

Harvesting Cells

Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm×25 cm) of cells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tube contains:

300 μl of assay buffer.

50 μl of [³H]-flumazenil (final concentration for α1β3μ2: 1.8 nM; for α2β3λ2: 1.8 nM; for α3β3λ2: 1.0 nM; for α5β3λ2: 1.0 nM).

50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 μM final concentration.

100 μl of cells.

Assays are incubated for 1 hour at 40° C., then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3×3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant K_(i) can be calculated for each test compound.

The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a K_(i) value for displacement of [³H]Ro 1.5-1788 from the α5 subunit of the human GABA_(A) receptor of 500 nM or less, preferably of 100 nM or less, and more particularly of 50 nM or less.

EXAMPLE 1 6.6-Dimethyl-1-(2-methyltetrazol-5-yl)-3-methnethylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1:6.6-Dimethyl-3-methyithio-1-(tetrazol-5-yl)-4,5,6,7-tetrahydrobenzol[c]thiophen-4-one

A solution of 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (156 mg, 0.6 mmol), sodium azide (117 mg, 1.8 mmol) and triethylamine hydrochloride (124 mg, 0.9 mmol) in N-methylpyrrolidinone (4 mL) was heated at relux for 2 h. After cooling to room temperature, hydrochloric acid (1 M) was added and the precipitate collected by filtration and washed with ether. The tetrazole (152 mg, 86%) was isolated as a tan solid. mp 268-27020 C. Found; C, 49.16: H, 4.75; N, 18.67%. C₁₂H₁₄N₄S₂O requires: C, 48.96; H, 4.79; N, 19.03%. ¹HNMR (360 MHz, d₆-DMSO) δ 1.02 (6H, s), 2.43 (2H, s), 2.66 (3H, s), 3.05 (2H, s). MS (ES⁺) 295 (M+1).

Step 2; 6,6-Dimethyl-1-(2-methyltetrazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To solution of 6,6-dimethyl-3-methylthio-1-(tetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (62 mg, 0.21 mmol) in DMF (5 mL) containing triethylamine (58 μL, 0.42 mmol) was added iodomethane (13 μL, 0.21 mmol). After stirring for 1 h more iodomethane (39 μL, 0.63 mmol) was added and stirring continued overnight. Ethyl acetate (20 ml) and water (20 mL) were added and the organic layer separated, dried (Na₂SO₄) and evaporated. The residue was triturated with CH₂Cl₂:EtOAc (1:1) and the undissolved solid (26 mg; 0.08 mmol) collected by filtration and washed with EtOAc. The filtrate was chromatographed on silica gel, eluting with petrol:EtOAc (2:) to give the title compound (10 mg, 0.03 mmol) as a tan solid. Total mass=36 mg (56%), mp 233-235° C. Found C, 50.26; H, 5.23; N, 17.94%. C₁₃H₁₆N₄S₂O requires: C,50.63; H, 5.23; N, 18.17%. ¹HNMR (250 MHz, CDCl₃) δ 1.10 (6H, s), 2.45 (2H, s), 2.65 (3H, s), 3.11 (2H, s), 4.40 (3H, s). MS (ES⁺) 309 (M+1).

EXAMPLE 2 6,6-Dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of 6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (200 mg, 0.69 mmol) in CH₂Cl₂:dioxan (3:1; 9 mL) at −78° C. was added m-CPBA (169 mg (70% w/w); 0.69 mmol) portionwise. After addition the solution was diluted with CH₂Cl₂ (10 mL) and poured into NaHCO₃ (sat., 10 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was triturated in ether to give the sulphoxide (106 mg, 50%) as a cream solid. mp 206-210° C. ¹HNMR (360 MHz, CDCl₃) δ 1.09 (3H, s), 1.11 (3H, s), 2.42 (1H, d, J=17 Hz), 2.52 (1H, d, J=17 Hz), 2.95 (2H, s), 3.01 (3H, s), 6.54 (1H, s), 7.68 (1H, s). MS (ES⁺) 309 (M+1).

EXAMPLE 3 6,6-Dimethyl-3-ethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of the sulphoxide (122 mg, 0.4 mmol), prepared according to Example 2, in THF (7 mL) at −10° C. under nitrogen, was added ethylmagnesium bromide (0.79 mL of a 1.0 M solution in THF, 0.79 mmol). After addition the mixture was stirred at −10° C. for 1 h, then NH₄Cl (sat., 1 mL) was added. The cooling bath was removed and the mixture stirred at room temperature for 10 min. The mixture was then partitioned between EtOAc (15 mL) and water (15 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica, eluting with EtOAc:CH₂Cl₂ (6:1). The fractions containing the desired product were combined and evaporated and the residue triturated with ether. The title compound (6 mg, 6%) was isolated as a pale yellow solid. mp 152-155° C. ¹HNMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 1.34 (3H, t, J=7.4 Hz), 2.42 (2H, s), 2.87 (2H, s), 3.30 (2H, q, J=7.4 Hz), 6.49 (1H, d, J=2.2 Hz), 7.65 (1H, d, J=2.2 Hz). MS (ES⁺) 275 (M+1).

EXAMPLE 4 6,6-Dimethyl-3-methylthio-1-(2-proyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 1, using iodopropane, the title compound (26 mg, 32%) was isolated as a cream solid. mp 163-165° C. Found: C, 53.54; H, 5.67; N, 16.28%. C₁₅H₂₀N₄S₂O requires: C, 53.54; H, 5.99; N, 16.65%. ¹HNMR (360 MHz, d₆-DMSO) δ 0.92 (3H, t, J=7.4 Hz), 1.03 (6H, s), 1.95-2.02 (2H, m), 2.43 (2H, s), 2.66 (3H, s), 3.09 (2H, s), 4.70 (2H, t, J=7.0 Hz). MS (ES⁺) 337 (M+1).

EXAMPLE 5 6,6-Dimethyl-1-(1-methanesulphonylpyrazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of 6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (70 mg, 0.24 mmol) in CH₂Cl₂:THF (5:1, 6 mL), was added methanesulphonyl chloride (36 μL, 0.48 mmol) and 4-dimethylaminopyridine (58 mg, 0.48 mmol). The mixture was stirred at room temperature overnight then diluted with CH₂Cl₂ (10 mL) and washed with water (2×10 mL). The organic layer was separated, dried (Na₂SO₁) and evaporated. The residue was chromatographed on silica gel, eluting with CH₂Cl₂:MeOH (95:5), to give the title compound (38 mg, 43%) as a pale yellow solid. mp 193-195° C. Found: C, 47.72; H, 4,71; N, 7.16%. C₁₅H₁₈N₂S₃O₃.0.3 (H₂O) requires: C, 47.93, H, 4.99; N, 7.45%. ¹HNMR (360 Hz, d₆-DMSO) δ 1.02 (6H, s), 2.41 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 3.61 (3H, s), 6.91 (1H, d, J=2.8 Hz). MS (ES⁺) 371 (M+1).

EXAMPLE 6 6,6-Dimethyl-3-(2-methylprop-1-yl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-6,6-dimethyl-3(2-methylprop-1-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of 1-cyano-6,6-dimethyl-3-methanesulphonyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (1.5 g, 5.3 mmol) in THF (15 mL) at −10° C. was added isobutylmagnesium chloride. After 1 h the cooling bath was removed and the mixture stirred at room temperature for 2 h. After this time the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with petrol: EtOAc (6:1), to give the title compound (526 mg, 38%) as an orange oil. ¹HNMR (360 MHz, CDCl₃) δ 0.97 (6H, d, J=6.6 Hz), 1.08 (6H, s), 1.94-2.02 (1H, m), 2,42 (2H, s), 2.85 (2H, s), 3.16 (2H, d, J=7.1 Hz).

Step 2: 6,6-Dimethyl-3-(2-methylprop-1-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen -4-one-1-thiocarboxamide

A solution of the nitrile (526 mg, 2.0 mmol) in pyridine (5 mL and triethylamine (0.3 mL) was treated with hydrogen sulphide for 20 min. After this time the solution was left to stand overnight. The solution was then poured into water (50 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with water then triturated with hexane. The desired thioamide (600 mg, 100%) was collected by filtration and isolated as a yellow solid. mp 153-156° C. Found: C, 61.11; H, 7.31; N, 4.77%. Calc: C, 60.98; H, 7.16; N, 4,74%. ¹HNMR (360 MHz, CDCl₃) δ 0.97 (6H, d, J=6.6 Hz), 1.07 (6H, s), 1.94-2.03 (1H, m), 2.40 (2H, s), 2.98 (2H, s), 3.12 (2H, d, J=7.0 Hz), 6.90 (1H, br s), 7.40 (1H, br s). MS (ES⁺) 296 (M+1).

Step 3: 6,6-Dimethyl-3-(2-methylprop-1-yl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

A solution of the thioamide (500 mg, 1.7 mmol) in EtOH (5 mL) was heated at relux, in the presence of chloroacetaldehyde (0.43 mL of a 50% (w/v) aqueous solution, 2.7 mmol), for 18 h. After this time the solvent was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with petrol: EtOAc (6:1→3:1), to give the thiazole (190 mg, 35%) as a beige solid. mp 98-100° C. Found: C, 64.29; H, 6.54; N, 4.37%. C₁₇H₂₁NOS₂ requires: C, 63.91; H, 6.63; N, 4.38%. ¹HNMR (360 MHz, CDCl₃) δ 0.99 (6H, d, J=6.6 Hz), 1.11 (6H, s), 1.99-2.07 (1H, m), 2.44 (2H, s), 2.94 (2H, s), 3.17 (2H, d, J=7.1 Hz), 7.35 (1H, d, J=3.4 Hz), 7.84 (1H, d, J=3.4 Hz). MS (ES⁺) 320 (M+1).

EXAMPLE 7 6,6-Dimethyl-3-isopropyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-6,6-dimethyl-3-isopropyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using isopropylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (1.2 g, 36%) was isolated as a colourless solid. mp 59-60° C. Found: C, 68.08; H, 6.97; N, 5.48%. C₁₄H₁₇NOS requires: C, 67.98; H, 6.93; N, 5.66%. ¹HNMR (360 MHz, CDCl₃) δ 1.08 (6H, s), 1.32 (6H, d, J=6.7 Hz), 2.43 (2H, s), 2.85 (2H, s), 4.24 (1H, heptet, J=6.7 Hz).

Step 2: 6,6-Dimethyl-3-isopropyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-6,6-dimethyl-3-isopropyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.58 g, 100%) was isolated as a yellow solid. mp 169-171° C. Found: C, 59,89; H, 6.64; N, 4.98%. C₁₄H₁₉NS₂O requires: C, 59.75; H, 6.81; N, 4.98%. ¹HNMR (250 MHz, CDCl₃) δ 1.08 (6H, s), 1.32 (6H, d, J=6.8 Hz), 2.41 (2H, s), 2.98 (2H, s), 4.23 (1H, heptet, J=6.8 Hz), 6.88 (1H, br s), 7.40 (1H, br s). MS (ES⁺) 282 (M+1).

Step 3: 6,6-Dimethyl-3-isopropyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 6,6-dimethyl-3-isopropyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (185 mg, 33%) was isolated as a cream solid. mp. 106-108° C. Found: C, 63.22; H, 6.17; N, 4.50%. C₁₆H₁₉NS₂O requires: C, 62.91; H, 6.27; N, 4.59%. ¹HNMR (360 MHz, CDCl₃) δ 1.11 (6H, s), 1.34 (6H, d, J=6.9 Hz), 2.45 (2H, s), 2.94 (2H, s), 4.27 (1H, heptet, J=6.9 Hz), 7.35 (1H, d, J=3.3 Hz), 7.83 (1H, d, J=3.3 Hz). MS (ES⁺) 306 (M+1).

EXAMPLE 8 6,6-Dimethyl-3-propyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-6,6-dimethyl-3-propyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using propylmagnesium chloride, the title compound (0.31 g, 36%) was isolated as an orange solid. mp 38-40° C. ¹HNMR (360 MHz, CDCl₃) δ 1.02 (3H, t, J=7.3 Hz), 1.08 (6H, s), 1.68-1.78 (2H, m), 2.42 (2H, s), 2.85 (2H, s), 3.25 (2H, t, J=7.6 HZ). MS (ES⁺) 248 (M+1).

Step 2: 6,6-Dimethyl-3-propyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-6,6-dimethyl-3-propyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (555 mg, 100%) was obtained as a yellow solid. mp 142-145° C. ¹HNMR (360 MHz, CDCl₃) δ 1.02 (3H, t, J=7.3 Hz), 1.08 (6H, s), 1.67-1.79 (2H, m), 2.40 (2H, s), 2.98 (2H, s), 3.21 (2H, t, J=7.6 Hz), 6.86 (1H, br s), 7.44 (1H, br s). MS (ES⁺) 282 (M+1).

Step 3: 6,6-Dimethyl-3-propyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 6,6-dimethyl-3-propyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (185 mg, 34%) was isolated as a pale yellow solid. mp 69-72° C. Found: C, 63.31; H, 6.17; N, 4.62%. C₁₆H₁₉NOS₂ requires: C, 62.91; H, 6.27; N, 4.59%. ¹HNMR (360 MHz, CDCl₃) δ 1.03 (3H, t, J=7.4 Hz), 1.11 (6H, s), 1.70-1.82 (2H, m), 2.45 (2H, s), 2.94 (2H, s), 3.26 (2H, t, J=7.5 Hz), 7.35 (1H, d, J=3.2 Hz), 7.84 (1H, d, J=3.4 Hz). MS (ES⁺) 306 (M+1).

EXAMPLE 9 6,6-Dimethyl-3-phenyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-6,6-dimethyl-3-phenyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using phenylmagnesium bromide, the title compound (0.17 g, 86%) was isolated as a cream solid. mp 100-103° C. ¹HNMR (250 MHz, CDCl₃) δ 1.13 (6H, s), 2.47 (2H, s), 2.94 (2H, s), 7.40-7.48 (3H, m), 7.54-7.58 (2H, m).

Step 2: 6,6-Dimethyl-3-phenyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-6,6-dimethyl-3-phenyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (532 mg, 94%) was obtained as a yellow solid. mp 202-204° C. ¹HNMR (360 MHz, CDCl₃) δ 1.12 (6H, s), 2.44 (2H, s), 3.05 (2H, s), 7.38-7.42 (3H, m), 7.52-7.55 (2H, m). MS (ES⁺) 316 (M+1).

Step 3: 6,6-Dimethyl-3-phenyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 6,6-dimethyl-3-phenyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (75 mg, 24%) was isolated as a cream solid. mp 141-143° C. Found: C, 67.45; H, 4.95; N, 4.17%. C₁₉H₁₇NOS₂ requires: C, 67.22; H, 5.05; N, 4.13%. ¹HNMR (360 MHz, CDCl₃) δ 1.16 (6H, s), 2.49 (2H, s), 3.03 (2H, s), 7.39-7.42 (4H, m), 7.59-7.63 (2H, m), 7.88 (1H, d, J=3.3 Hz). MS (ES⁺) 340 (M+1).

EXAMPLE 10 3-Cyclohexyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-3-cyclohexyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using cyclohexylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.63 g, 28%) was isolated as a cream solid. mp 129-132° C. ¹HNMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 1.20-1.55 (5H, m), 1.75-1.85 (3H, m), 2.01-2.06 (2H, m), 2.42 (2H, s), 2.84 (2H, s), 3.85-3.94 (1H, M).

Step 2: 3-Cyclohexyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-3-cyclohexyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (614 mg, 100%) was obtained as a yellow solid. mp 196-199° C. ¹HNMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 1.21-1.52 (5H, m), 1.73-1.84 (3H, m), 2.00-2.05 (2H, m), 2.40 (2H, s), 2.98 (2H, s), 3.84-3.92 (1H, m), 6.86 (1H, br s), 7.50 (1H, br s). MS (ES⁺) 322 (M+1).

Step 3: 3-Cyclohexyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 3-cyclohexyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (180 mg, 56%) was isolated as a green solid. mp 101-103° C. Found: C, 66.39; H, 6.58; N, 4.06%. C₁₉H₂₃NOS₂ requires: C, 66.05; H, 6.71; N, 4.05%. ¹HNMR (360 MHz, CDCl₃) δ 1.11 (6H, s), 1.23-1.50 (5H, m), 1.73-1.85 (3H, m), 2.04-2.09 (2H, m), 2.45 (2H, s), 2.94 (2H, s), 3.89-3.95 (1H, m), 7.34 (1H, d, J=3.4 Hz), 7.83 (1H, d, J=3.2 Hz). MS (ES⁺) 346 (M+1).

EXAMPLE 11 3-Cyclobutyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-3-cyclobutyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using cyclobutylmagnesium bromide and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.37 g, 18%) was isolated as a pale yellow solid. mp 65-68° C. ¹HNMR (360 MHz, CDCl₃) δ 1.06 (6H, s), 1.90-1.98 (1H, m), 2.00-2.12 (3H, m), 2.40 (2H, s), 2.50-2.62 (2H, m), 2.83 (2H, s), 4.45-4.56 (1H, m).

Step 2: 3-Cyclobutyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-3-cyclobutyl-6,6-dimehtyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (309 mg, 74%) was obtained as a yellow solid. mp 212-215° C. ¹HNMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 1.84-1.96 (1H, m), 2.00-2.16 (3H, m), 2.38 (2H, s), 2.50-2.58 (2H, m), 2.96 (2H, s), 4.40-4.50 (1H, m). MS (ES⁺) 294 (M+1).

Step 3: 3-Cyclobutyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 3-cyclobutyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (273 mg, 86%) was isolated as a blue/green solid. mp 126-128° C. Found: C, 63.84; H, 5.98; N, 4.31%. C₁₇H₁₉NOS₂.0.1 (H₂O) requires: C, 63.95; H, 6.06; N, 4.93%. ¹HNMR (360 MHz, CDCl₃) δ 1.10 (6H, s), 1.90-1.96 (1H, m), 2.04-2.20 (3H, m), 2.42 (2H, s), 2.50-2.60 (2H, m), 2.93 (2H, s), 4.50-4.60 (1H, m), 7.35 (1H, d, J=3.2 Hz), 7.84 (1H, d, J=3.2 Hz). MS (ES⁺) 318 (M+1).

EXAMPLE 12 3-(But-3-enyl)-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 3-(But-3-enyl)-1-cyano-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using 3-butenylmagnesium bromide, the title compound (0.95 g, 70%) was isolated as a pale yellow solid. mp 43-46° C. ¹HNMR (250 MHz, CDCl₃) δ 1.08 (6H, s), 2.40-2.50 (4H, m), 2.85 (2H, s), 3.38 (2H, t, J=10.5 Hz) 5.01-5.10 (2H, m), 5.74-5.90 (1H, m). MS (ES⁺) 260 (M+1).

Step 2: 3-(But-3-enyl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 3-(but-3-enyl)-1-cyano-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (559 mg, 99%) was obtained as a yellow solid. mp 125-128° C. ¹HNMR (360 MHz, CDCl₃) δ 1.08 (6H, s), 2.40-2.48 (4H, m), 2.98 (2H, s), 3.34 (2H, t, J=7.4 Hz), 5.00-5.09 (2H, m), 5.79-5.91 (1H, m), 6.86 (1H, br s), 7.42 (1H, br s). MS (ES⁺) 294 (M+1).

Step 3: 3-(But-3-enyl)-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 3-(but-3-enyl)-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (0.21 g, 66%) was isolated as a cream solid. mp 62-65° C.

Found: C, 64.40; H, 6.08; N, 4.44%. C₁₇H₁₉NOS₂ requires: C, 64.32; H, 6.03; N, 4.41%. ¹HNMR (360 MHz, CDCl₃)δ 1.11 (6H, s), 2.45-2.52 (4H, m), 2.94 (2H, s), 3.39 (2H, t, J=7.3 Hz), 4.99-5.10 (2H, m), 5.82-5.94 (1H, m), 7.35 (1H, d, J=3.4 Hz), 7.84 (1H, d, J=3.4 Hz). MS (ES⁺) 318 (M+1).

EXAMPLE 13 3-Cyclopropyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-3-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using cyclopropylmagnesium bromide, the title compound (0.48 g, 29%) was isolated as a yellow solid. mp 80-83° C. ¹HNMR (360 MHz, CDCl₃)δ 0.82 (2H, m), 1.09 (6H, s), 1.31-1.36 (2H, m), 2.45 (2H, s), 2.82 (2H, s), 3.34-3.42 (1H, m). MS (ES⁺) 246 (M+1).

Step 2: 3-Cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-3-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (536 mg, 94%) was obtained as a yellow solid. mp 196-199° C. ¹HNMR (360 MHz, CDCl₃)δ 0.86-0.92 (2H, m), 1.09 (6H, s), 1.26-1.32 (2H, m), 2.43 (2H, s), 2.94 (2H, s), 3.33-3.40 (1H, m). MS (ES⁻) 280 (M+1).

Step 3: 3-Cyclopropyl-6,6-dimethyl-1-(thiazol-2yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 3-cyclopropyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (195 mg, 64%) was isolated as a cream solid. mp 103-105° C.

Found: C, 63.47; H, 5.65; N, 4.58%. C₁₆H₁₇NOS₂ requires: C, 63.33; H, 5.65; N, 4.62%. ¹HNMR (360 MHz, CDCl₃)δ 0.85-0.91 (2H, m), 1.13 (6H, s), 1.24-1.31 (2H, m), 2.47 (2H, s), 2.91 (2H, s), 3.36-3.42 (1H, m), 7.33 (1H, d, J=3.4 Hz), 7.80 (1H, d, J=3.2 Hz). MS (ES⁺) 304 (M+1).

EXAMPLE 14 6,6-Dimethyl-3-(2-methylprop-1-enyl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-thione Step 1: 1-Cyano-6,6-dimethyl-3-(2-methylprop-1-enyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 1, using 2-methyl-1-propenylmagnesium bromide, the title compound (0.59 g, 43%) was isolated as a pale yellow solid. mp 115-117° C. ¹HNMR (360 MHz, CDCl₃)δ 1.08 (6H, s), 2.07 (6H, s), 2.44 (2H, s), 2.85 (2H, s), 7.64-7.65 (1H, m), MS (ES⁺) 260 (M+1).

Step 2: 6,6-Dimethyl-3-(2-mercapto-2-methylpropyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano-6,6-dimethyl-3-(2-methylprop-1-enyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (635 mg, 100%) was obtained as a yellow solid. mp 156-165° C. ¹HNMR (360 MHz, CDCl₃)δ 1.08 (6H, s), 1.44 (6H, s), 2.41 (2H, s), 3.02 (2H, s), 3.71 (2H, s), 6.92 (1H, br s), 7.50 (1H, br s), MS (ES⁺) 328 (M+1).

Step 3: 6,6-Dimethyl-3-(2-methylprop-1-enyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-thione-1-thiocarboxamide

A solution of the thiol (300 mg, 0.92 mmol) in THF (20 ml) and HCl (1M, 5 ml) was heated at reflux for 2 h. After cooling, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The two layers were separated and the aqueous extracted with EtOAc (50 mL). The combined organic layers were dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of EtOAc: hexane (1:3) to EtOAc:hexane (1:1). The fractions containing the desired product were combined and evaporated to afford the title compound (0.2 g, 71%) as a yellow solid. mp 225-228° C. ¹HNMR (250 MHz, CDCl₃)δ 1.12 (6H, s), 1.38 (6H, s), 2.95 (2H, s), 2.98 (2H, s), 5.60 (1H, s), 6.82 (1H, br s), 7.34 (1H, br s), MS (ES⁺) 310 (M+1).

Step 4: 6,6-Dimethyl-3-(2-methylprop-1-enyl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophenp4-thione

In the same was as described in Example 6, Step 3, using 6,6-dimethyl-3-(2-methylprop-1-enyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-thione-1-thiocarboxamide, the thiazole (150 mg, 93%) was obtained as a pale yellow solid. mp 114-116° C.

Found: C, 61.24; H, 5.60; N, 4.19%, C₁₇H₁₉NS₃ requires: C, 61.22; H, 5.74; N, 4.20%. ¹HNMR (360 MHz, CDCl₃)δ 1.15 (6H, s), 1.41 (6H, s), 2.93 (2H, s), 3.02 (2H, s), 5.60 (1H, s), 7.30 (1H, d, J=3.4 Hz), 7.81 (1H, d, J=3.2 Hz), MS (ES⁺) 334 (M+1).

EXAMPLE 15 3-Methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydro[c]thiophen-4-one

A mixture of 1-bromo-3-methylthio-4,5,6,7-tetrahydro[c]thiophen-4-one (0.1 g, 0.36 mmol) and 2-(tri-n-butylstannyl)pyridine (0.19 g, 0.52 mmol) in dioxane (10 mL) was purged with nitrogen for 20 min. Dichlorobis(triphenylphosphine)palladium (II) (10 mg) was added and the mixture heated at reflux for 4 h. Further dichlorobis(triphenylphosphine)palladium (II) (10 mg) was added and the mixture heated at reflux for 20 h. further catalyst (10 mg) and 2-(tri-n-butylstannyl) pyridine (66 mg, 0.18 mmol) were added and the mixture heated at reflux for 6 h. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel, eluting with EtOAc:hexane (1:2). The fractions containing the desired product were combined and evaporated and the residue triturated with ether. The title compound (28 mg, 28%) was isolated as a yellow solid. mp 188-190° C.

Found: C, 60.98; H, 4.59; N, 4.83%. C₁₄H₁₃NOS₂ requires: C, 61.06; H, 4.76; N, 5.09%. ¹HNMR (360 MHz, CDCl₃)δ 2.07-2.14 (2H, m), 2.57-2.61 (2H, m), 2.65 (3H,s), 3.10 (2H, t, J=6.1 Hz), 7.14-7.18 (1H, m), 7.48 (1H, d, J=8.1 Hz), 7.70-7.75 (1H, m), 8.59-8.62 (1H, m), MS (ES⁺) 276 (M+1).

EXAMPLE 16 6,6-Dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of 6,6-dimethyl-3-methylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (2 g, 6.8 mmol) in CH₂Cl₂:dioxan (3:1:195 mL) at −78° C. was added m-CPBA (3.38 g (70% w/w), 13.6 mmol) portionwise. The mixture was stirred at −78° C. for 30 min and then allowed to warm to room temperature. After stirring for 2 h, the mixture was poured into NaHCO₃ (sat., 100 mL). The organic layer was separated and washed with NaHCO₃ (sat., 2×100 mL), dried (Na₂SO₁) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc:hexane (1:1) followed by EtOAc. The fractions containing the desired product were combined and evaporated and the residue triturated with ether. The title compound (1.77 g, 80%) was isolated as a cream solid. mp 213-216° C.

Found: C, 50.48; H, 4.67; N, 8.16%. C₁₄H₁₆N₂O₃S₂.0.15(CH₂Cl₂) requires: C, 50.41; H, 4.87; N, 8.31%. ¹HNMR (360 MHz, CDCl₃)δ 1.12 (6H, s), 2.55 (2H, s), 2.98 (2H, s), 3.55 (3H , s), 6.58 (1H, d, J=2.6 Hz), 7.69 (1H, d, J=2.4 Hz). MS (ES⁺) 325 (M+1).

EXAMPLE 17 1-(Thiazol-2-yl)-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 6, Step 1, using methylmagnesium bromide, the title compound (0.8 g, 69%) was isolated as a colourless solid. mp 73-75° C.

Found: C, 65.96; H, 5.86; N, 6.39%. C₁₂H₁₃NOS requires: C, 65.72; H, 5.98; N, 6.39%. ¹HNMR (250 MHz, CDCl₃)δ 1.08 (6H, s), 2.42 (2H, s), 2.82 (3H, s), 2.85 (2H, s).

Step 2: 3,6,6-Trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as that described in Example 6, Step 2, using 1-cyano-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, gave the thioamide (0.478 g, 100%) as a yellow solid. mp 193-195° C. ¹HNMR (250 MHz, CDCl₃)δ 1.08 (6H, s), 2.41 (2H, s), 2.78 (3H, s) 2.97 (2H, s), 6.88 (1H, br s), 7.49 (1H, br s). MS (ES⁺) 254 (M+1).

Step 3: 1-(Thiazol-2-yl)-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 6, Step 3, using 3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (186 mg, 40%) was isolated as a colourless solid. mp 98-100° C.

Found: C, 60.93; H, 5.35; N, 5.11%. C₁₄H₁₅NO₂S₂ requires: C, 60.62; H, 5.45; N, 5.05%. ¹HNMR (360 MHz, CDCl₃)δ 1.17 (6H, s), 2.45 (2H, s), 2.82 (3H, s), 2.93 (2H, s), 7.34 (1H, d, J=3.2 Hz), 7.83 (1H, d, J=3.2 Hz). MS (ES⁺) 278 (M+1).

EXAMPLE 18 3-Benzyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 3-Benzyl-1-cyano-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 6, Step 1, using benzylmagnesium bromide, the title compound (360 mg, 20%) was isolated as a colourless solid. ¹HNMR (360 MHz, CDCl₃)δ 1.09 (6H, s), 2.46 (2H, s), 2.85 (2H, s), 4.60 (2H, s), 7.26-7.34 (5H, m).

Step 2: 3-Benzyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as that described in Example 6, Step 2, using 3-benzyl-1-cyano-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the thioamide (470 mg, 100%) was isolated as a yellow solid. mp 183-185° C.

Found: C, 63.25; H, 5.57; N, 4.21%. C₁₈H₁₉NOS₂. 0.6 (H₂O) requires: C, 63.53; H, 5.98; N, 4.12%. ¹HNMR (250 MHz, CDCl₃)δ 1.09 (6H, s), 2.44 (2H, s), 3.00 (2H, s), 4.57 (2H, s), 6.82 (1H, br s), 7.20-7.36 (5H, m), 7.42 (1H, br s), MS (ES⁺) 330 (M+1).

Step 3: 3-Benzyl-6,6′-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 6, Step 3, using 3-benzyl-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (153 mg, 42%) was isolated as a colourless solid. mp 112-113° C.

Found: C, 68.14; H, 5.28; N, 4.0%. C₂₀H₁₉NOS₂ requires: C, 67.95; H, 5.42; N, 3.96%. ¹HNMR (360 MHz, CDCl₃)δ 1.13 (6H, s), 2.48 (2H, s), 2.94 (2H, s), 4.62 (2H, s), 7.21-7.33 (6H, m), 7.79 (1H, d, J=3.3 Hz). MS (ES⁺) 354 (M+1).

EXAMPLE 19 6,6-Dimethyl-3-methylthio-01-((1-phenylsulphonyl)pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 5, using benzenesulphonyl chloride, the title compound (51 mg, 49%) was isolated as a colourless solid. mp 200-202° C.

Found: C, 55.58; H, 4.41; N, 6.19%. C₂₀H₂₀N₂O₃S₃ requires: C, 55.53; H, 4.66; N, 6.48%. ¹HNMR (360 MHz, CDCl₃)δ 1.04 (6H, s), 2.40 (2H, s), 2.61 (3H, s), 2.80 (2H, s), 6.53 (1H, d, J=2.7 Hz), 7.56 (2H, t, J=7.5 Hz), 7.67 (1H, t, J=7.6 Hz), 8.07 (2H, d, J=7.3 Hz), 8.13 (1H, d, J=2.7 Hz). MS (ES⁺) 433 (M+1).

EXAMPLE 20 6,6-Dimethyl-3-isopropylthio-1-(2-methyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-isopropylthio-1-(tetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 1, Step 1, using 1-cyano-6,6-dimethyl-3-isopropylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the tetrazole (360 mg, 62%) was isolated as a yellow solid. mp 228-230° C.

Found: C, 52.17; H, 5.51; N, 17.34%. C₁₄H₁₈N₄OS₂ requires: C, 52.15; H, 5.63; N, 17.38%. ¹HNMR (360 MHz, d₆-DMSO)δ 1.06 (6H, s), 1.46 (6H, d, J=6.6 Hz), 2.43 (2H, s), 3.05 (2H, s), 3.59 (1H, heptet, J=6.6 Hz). MS (ES⁺) 323 (M+1).

Step 2: 6,6-Dimethyl-3-isopropylthio-1-(2-methyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 1, Sep 2, the title compound (32 mg, 44%) was isolated as a yellow solid. mp 180-183° C.

Found: C, 53.37; H, 5.73; N, 15.96%. C₁₅H₂₀N₄OS₂. 0.2 (H₂O) requires: C, 52.98; H, 6.05, N, 16.47%. ¹HNMR (250 MHz, d₆-DMSO)δ 0.98 (6H, s), 1.45 (6H, d, J=6.6 Hz), 2.43 (2H, s), 3.07 (2H, s), 3.59 (1H, heptet, J=6.6 Hz), 4.42 (3H, s). MS (ES⁺) 337 (M+1).

EXAMPLE 21 1-(1-Acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 2, using 1-(1-acetylpyrazol-3-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the sulphoxide (91 mg. 58%) was isolated as a colourless solid. mp 195-197° C.

Found: C, 55.23; H, 5.05; N, 7.86%. C₁₆H₁₈N₂O₃S₂ requires: C, 54.84; H, 5.18; N, 7.99%. ¹HNMR (360 MHz, CDCl₃)δ 1.11 (3H, s), 1.13 (3H, s), 2.43 (1H, d, J=16.6 Hz), 2.53 (1H, d, J=16.6 Hz), 2.76 (3H, s), 2.99 (2H, s), 3.01 (3H, s), 6.67 (1H, d, J=2.9 Hz), 8.33 (1H, d, J=2.9 Hz). MS (ES⁺) 351 (M+1).

EXAMPLE 22 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as that described in Example 6, Steps 1 and 2, using 2-hydroxyethylmagnesium bromide and 1-cyano-6,6-dimethyl-3-[(2-hydroxyethyl) thio]-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the thioamide (511 mg, 100%) was isolated as a pale yellow solid. ¹HNMR (250 MHz, d₆-DMSO)δ 1.05 (6H, s), 2.35 (2H, s), 2.91 (2H, s), 3.17 (2H, t, J=6.3 Hz), 3.71-3.78 (2H, m), 5.16 (1H, t, J=5.5 Hz), 8.70 (1H, br s), 9.85 (1H, br s). MS (ES⁺) 316 (M+1).

Step 2: 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 6, Step 3, using 6,6-dimethyl-3-[(2-hydroxyethyl)thio]-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the thiazole (247 mg, 47%) was isolated as a pale yellow solid. mp 168-170° C.

Found: C, 52.17; H, 5.14; N, 3.99%. C₁₅H₁₇NS₃O₂.0.2 (H₂O) requires: C, 52.51; H, 5.11; N, 4.08%. ¹HNMR (360 Hz, CDCl₃)δ 1.12 (6H, s), 2.47 (2H, s), 2.90 (2H, s), 3.32 (2H, t, J=5.9 Hz), 4.01 (2H, t, 5.9 Hz), 7.36 (1H, d, J=3.2 Hz), 7.82 (1H, d, J=3.2 Hz). MS (ES⁺)340 (M+1).

EXAMPLE 23 6,6-dimethyl-3-[(1,1-dimethylethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of 1-(1-acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (73 mg, 0.21 mmol) in THF (7 mL) was added sodium 2-methyl-2-propanethiolate (47 mg, 0.42 mmol). After 90 min more sodium 2-methyl-2-propanethiolate (15 mg, 0.14 mmol) was added, and after a further 30 min the mixture was partitioned between EtOAc (15 mL) and water (10 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1), to give the title compound (34 mg, 48%) as a yellow solid. mp 220-222° C.

Found: C, 60.67; H, 6.39; N, 8.31%. C₁₇H₂₂N₂OS₂ requires: C, 61.04; H, 6.63; N, 8.37%. ¹NHMR (360 Hz, d₆-DMSO)δ 1.00 (6H, s), 1.45 (9H, s), 2.39 (2H, s), 2.88 (2H, s), 6.54 (1H, br s), 7.87 (1H, br s), 13.07 (1H, br s). MS (ES⁺) 335 (M+1).

EXAMPLE 24 6,6-Dimethyl-3-methoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a stirred solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (80 mg, 0.26 mmol) in methanol (3 mL) was added a solution of sodium methoxide in methanol (1.0 mL of a 0.5M solution, 0.5 mmol). The solution was heated at 70° C. for 24 h. after which time the mixture was cooled to room temperature and partitioned between EtOAc (2×20 mL) and water (20 mL). The combined organic layers were dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with CH₂Cl₂:MeOH (95:5), to give the title compound (11 mg, 15%) as a pale yellow solid. mp 202-204° C. Found: C, 60.24; H, 5.66; N, 10.06%. C₁₄H₁₆N₂O₂S.0.1 (H₂O) requires: C, 60.45; H, 5.87; N, 10.07%. ¹HNMR (360 MHz, d₆-DMSO)δ 0.98 (6H, s), 2.27 (2H, s), 2.79 (2H, s), 4.03 (3H, s), 6.54 (1H, br s), 7.81 (1H, br s), 12.92 (1H, br s). MS (ES⁺) 277 (M+1).

EXAMPLE 25 6,6-Dimethyl-1-(4-methyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboximidic acid ethyl ester hydrochloride

A solution of 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1.19 mmol) in saturated ethanolic hydrogen chloride solution (50 mL) was stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate. The product was filtered off, washed with ether and dried to yield the title compound as a white solid (350 mg, 98%). mp 134-136° C. ¹HNMR (250 MHz, d₆-DMSO)δ 1.00 (6H, s), 1.44 (3H, t, J=7.0 Hz), 2.45 (2H, s), 2.67 (3H, s), 3.00 (2H, s), 4.52 (2H, q, J=7.0 Hz). MS (ES⁺) 298 (M+1).

Step 2: Formic acid[ethoxy-(6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophen-1-yl)methylene]hydrazide

A solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboximide acid ethyl ester hydrochloride (350 mg, 1.2 mmol) in ethanol (10 mL) was treated with formylhydrazine (70 mg, 1.2 mmol). The mixture was stirred for 16 h at 20° C. then warmed to 50° C. for 4 h. The solvent was removed in vacuo and the residue was purified by chromatographed on silica gel, eluting with methanol:dichloromethane (5.95). The title compound was obtained as a pale yellow oil (150 mg; 38%). ¹HNMR (360 MHz, CDCl₃)δ 1.06 (6H, s), 1.36 (3H, t, J=7.2 Hz), 2.41 (2H, s), 2.60 (3H, s), 2.75 (2H, s), 4.07 (2H, q, J=7.2 Hz), 8.65 (1H, s). MS (ES⁺) 341 (M+1).

Step 3: 6,6-Dimethyl-1-(4-methyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

Formic acid[ethoxy-(6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophen-1-yl)methylene]hydrazide (150 mg, 0.49 mmol) was dissolved in a solution of methylamine in ethanol (30%, 10 mL) and the mixture heated at 60° C. More methylamine solution (10 mL) was added periodically over 8 h. The solution was evaporated to dryness and the residue purified by chromatographed on silica gel, eluting with methanol:dichloromethane (5:95). The title compound was obtained as a white powder (60 mg, 44%). mp 178-180° C. Found: C, 52.50; H, 5.43; N, 12.73%. C₁₄H₁₇N₃OS₂.0.8 (H₂O) requires: C, 52.25; H, 5.83; N, 13.06%. ¹HNMR (360 MHz, CDCl₃)δ 1.05 (6H, s), 2.44 (2H, s), 2.62 (3H, s), 2.79 (2H, s), 3.75 (3H, s), 8.28 (1H, s). MS (ES⁺) 308 (M+1).

EXAMPLE 26 6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as in Example 6, Step 2 using 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound was isolated as a yellow solid (450 mg, 80%). mp 216-218° C. ¹HNMR (250 MHz, CDCl₃)δ 1.09 (6H, s), 2.41 (2H, s), 2.64 (3H, s), 2.91 (2H, s), Found: C, 50.67; H, 5.07; N, 4.88%. C₁₂H₁₅NOS₃ requires C, 50.50; H, 5.30; N, 4.91%. MS (ES⁺) 286 (M+1).

Step 2: 6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide and ethyl bromopyruvate, the title compound was isolated as a pale yellow solid (65 mg, 11%). mp 185-187° C. Found: C, 51.58; H, 4.87; N, 3.53%. C₁₇H₁₉NO₃S₃.0.75 (H₂O) requires: C, 51.69; H, 5.23; N, 3.55%. ¹HNMR (360 MHz, CDCl₃)δ 1.12 (6H, s), 1.42 (3H, t, J=7.2 Hz), 2.45 (2H, s), 2.65 (3H, s), 2.89 (2H, s), 4.44 (2H, q, J=7.2 Hz), 7.26 (1H, s), 8.13 (1H, s). MS (ES⁺) 382 (M+1).

EXAMPLE 27 6,6-Dimethyl-1-((4-trifluoromethyl)thiazol-2-yl)-3-methylthio-4,5,6,7tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 26, Step 2 using 1-bromo-3,3,3-trifluoropropanone, the title compound was isolated as a pale yellow solid (85 mg, 26%). mp 165-167° C. Found: C, 47.73; H, 3.91; N, 3.60%. C₁₅H₁₄F₃NOS₃ requires: C, 47.73; H, 3.74; N, 3.71%. ¹HNMR (360 MHz, CDCl₃)δ 1.13 (6H, s), 2.47 (2H, s), 2.65 (3H, s), 2.88 (2H, s), 7.72 (1H, s), MS (ES⁺) 378 (M+1).

EXAMPLE 28 6,6-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 6, Step 3, using 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the title compound was isolated as a pale yellow solid (350 mg, 65%). mp 149-151° C. Found: C, 52.41; H, 4.64; N, 4.59%. C₁₄H₁₅NOS₃.0.6 (H₂O) requires: C, 52.79; H, 5.06; N, 4.40%. ¹HNMR (360 MHz, CDCl₃)δ 1.12 (6H, s), 2.46 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 7.35 (1H, d, J=3.6 Hz), 7.81 (1H, d, J=3.6 Hz). MS (ES⁺) 310 (M+1).

EXAMPLE 29 6,6-Dimethyl-3-dimethylamino-1-((4-ethoxycarbonyl)thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (100 mg, 0.26 mmol), was dissolved in a solution of dimethylamine in ethanol (30%, 5 mL). The solution was heated in a sealed tube for 3 days at 50° C. The solvent was removed in vacuo and the residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (1:3). The title compounds was isolated as a colourless solid (43 mg, 43%). mp 120-122° C. Found: C, 56.13; H, 5.76; N, 6.53%. C₁₈H₂₂N₂O₃S₂.0.4 (H₂O) requires: C, 56.05; H, 5.96; N, 6.26%. ¹HNMR (360 MHz, CDCl₃)δ 1.11 (6H, s), 1.41 (3H, t, J=7.2 Hz), 2.40 (2H, s), 2.84 (2H, s), 3.16 (6H, s), 4.42 (2H, q, J=7.2 Hz), 8.03 (1H, s). MS (ES⁺) 379 (M+1).

EXAMPLE 30 1-((4-Acetyl)thiazol-2-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 26, Step 2, using 1-bromo-2,3-butanedione, the title compound was isolated as a beige solid (0.21 g, 34%). mp 195-197° C. Found: C, 54.36; H, 4.57; N, 3.91%. C₁₆H₁₇NO₂S₃ requires: C, 54.67; H, 4.87; N, 3.98%. ¹HNMR (360 MHz, CDCl₃)δ 1.12 (6H, s), 2.46 (2H, s), 2.67 (3H, s), 2.71 (3H, s), 2.90 (2H, s), 8.10 (1H, s). MS (ES⁺) 352 (M+1).

EXAMPLE 31 6,6-Dimethyl-1-((4-methyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same was as Example 26, Steps 1 and 2, using isopropylmagnesium bromide an chloroacetone, the title compound was isolated as a beige solid (0.11 g, 18%). mp 183-185° C. Found: C, 54.57; H, 5.06; N, 4.36%. C₁₅H₁₇NOS₃.0.4(H₂O) requires: C, 54.78; 5.39; N, 4.26%. ¹HNMR (360 MHz, CDCl₃)δ 1.11 (6H, s), 2.44 (2H, s), 2.48 (3H, s), 2.64 (3H, s), 2.86 (2H, s), 6.89 (1H, s). MS (ES⁺) 324 (M+1).

EXAMPLE 32 6,6-Dimethyl-3-isopropylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-isopropylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as in Example 6, Step 2, using 1-cyano-6,6-dimethyl-3-isopropylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound was isolated as a yellow solid (1.9 g, 85%). mp 185-187° C. ¹HNMR (360 MHz, CDCl₃)δ 1.08 (6H, s), 1.51 (6H, d, J=7.2 Hz), 2.40 (2H, s), 2.90 (2H, s), 3.59 (1H, heptet, J=7.2 Hz). MS (ES⁺) 314 (M+1).

Step 2: 6,6-Dimethyl-3-isopropylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 6, Step 3, using 6,6-dimethyl-3-isopropylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the title compound was isolated as a beige solid (0.24 g, 46%). mp 202-204° C. Found: C, 57.18; H, 5.52; N, 4.21%. C₁₆H₁₉NOS₃ requires: C, 56.94; H, 5.67; N, 4.15%. ¹HNMR (250 MHz, CDCl₃)δ 1.12 (6H, s), 1.53 (6H, d, J=7.5 Hz), 2.46 (2H, s), 2.88 (2H, s), 3.59 (1H, heptet, J=7.5 Hz), 7.35 (1H, d, J=3.3 Hz), 7.82 (1H, d, J=3.3 Hz). MS (ES⁻) 338 (M+1).

EXAMPLE 33 6,6-Dimethyl-3-methylthio-1-(pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-1-((1-triphenylmethyl)pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of 1-bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (76 mg, 0.25 mmol) in water (3 mL) and ethylene glycol dimethyl ether (5 mL) was added (1-triphenylmethyl)pyrazol-4-yl boronic acid (115 mg, 0.32 mmol) and sodium carbonate (68 mg, 0.64 mmol). The solution was degassed by bubbling nitrogen through it, then tetrakis (triphenylphosphine) palladium (147 mg, 0.12 mmol) was added and the mixture refluxed for 10 h. The solution was then diluted with 10% sodium carbonate solution and extracted twice with ethyl acetate (10 mL). The combined extracts were dried (Na₂SO₄) and evaporated to dryness. The residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (1:4). The title compound was obtained as a yellow solid (45 mg, 34%). ¹HNMR (360 MHz, CDCl₃)δ 1.01 (6H, s), 2.37 (2H, s), 2.50-2.58 (5H, m), 7.17-7.25 (6H, m), 7.33-7.35 (9H, m), 7.43, (1H, s), 7.75 (1H, s).

Step 2: 6,6-Dimethyl-3-methylthio-1-(pyrazol-4-yl)-4,5,6,7tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-methylthio-1-((1-triphenylmethyl)pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (35 mg, 0.065 mmol) was dissolved in 98% formic acid (1 mL) and stirred at room temperature for 4 h. The solution was diluted with water and extracted with ethyl acetate (2×5 mL). The extracts were washed with dilute potassium carbonate solution and brine, then dried (Na₂SO₄). After evaporation to dryness, the residue was washed twice with diethyl ether to yield the title compound as a yellow powder (10 mg, 52%). mp 213-215° C. ¹HNMR (360 MHz, CDCl₃)δ 1.05 (6H, s), 2.41 (2H, s), 2.60 (3H, s), 2.68 (2H, s), 7.25 (1H, s), 7.71 (1H, s). MS (ES⁺) 293 (M+1).

EXAMPLE 34 6,6-Dimethyl-3-methylthio-1-(pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-1-((1-tert-butyloxycarbonyl)pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same was as in Example 33, Step 1, using (1-tert-butyloxycarbonyl)pyrrol-2-yl boronic acid, the title compound was isolated as a pale yellow solid (80 mg, 20%). mp 165-167° C. Found: C, 60.85; H, 6.36, N, 3.55%. C₂₀H₂₅NO₃S₂ requires: C, 60.79; H, 6.48; N, 3.54%. ¹HNMR (360 MHz, CDCl₃)δ 1.00 (6H, s), 1.42 (9H, s), 2.37 (2H, s), 2.45 (2H, s), 2.57 (3H, s), 6.23-6.26 (2H, m), 7.41 (1H, t, J=2.2 Hz). MS (ES⁺) 392 (M+1).

Step 2: 6,6-Dimethyl-3-methylthio-1-(pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-methylthio-1-((1-tert-butyloxycarbonyl)pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (80 mg, 0.20 mmol) was dissolved in trifluoracetic acid (5 mL) and allowed to stand at 20° C. for 30 min. The solvent was removed in vacuo and the residue dissolved in ethyl acetate. The solution was washed with dilute sodium carbonate solution, water and brine and dried (Na₂SO₄). The solution was evaporated to dryness and the residue purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (1:4). The title compound was isolated as a yellow solid (35 mg, 59%). mp 159-197° C. Found: C, 61.64; H, 6.05; N, 4.68%. C₁₅H₁₇NOS₂ requires: C, 61.82; H, 5.88; N, 4.81%. ¹HNMR (360 MHz, CDCl₃)δ 1.04 (6H, s), 2.40 (2H, s), 2.59 (3H, s), 2.73 (2H, s), 6.30-6.33 (2H, m), 6.85-6.88 (1H, m), 8.23 (1H, br s). MS (ES⁺) 292 (M+1).

EXAMPLE 35 6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

1-Bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1 mmol) was dissolved in dioxane (25 mL), and 2-(tri-n-butylstannyl)pyridine (550 mg, 1.35 mmol) was added. The solution was degassed with nitrogen then tetrakis (tri-phenylphosphine)palladium (30 mg, 0.025 mmol) was added and the solution refluxed for 16 h. The solvent was then removed in vacuo and the residue triturated with a mixture of ethyl acetate and hexane (1:3). After filtration the solid product was washed with a little diethyl ether to give the title compound as a white solid (170 mg, 57%). mp 217-220° C. Found: C, 63.02; H, 5.64; N, 4.47%. C₁₆H₁₇NOS₂ requires; C, 63.36; H, 5.61; N, 4.62%. ¹HNMR (250 MHz, CDCl₃)δ 1.08 (6H, s), 2.44 (2H, s), 2.65 (3H, s), 2.93 (2H, s), 7.18 (1H, m), 7.47 (1H, d, J=8 Hz), 7.71-7.77 (1H, m), 8.61-8.63 (1H, m). MS (ES⁺) 304 (M+1).

EXAMPLE 36 6,6-Dimethyl-3-((2-hydroxyethyl)thio)-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methanesulphinyl-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (200 mg, 0.66 mmol) was dissolved in CH₂Cl₂ (20 mL) and cooled to −78° C. Meta-chloroperoxybenzoic acid (82 mg of 70% (w/w); 0.66 mmol) was dissolved in CH₂Cl₂ (5 mL) and added dropwise to the solution, which was allowed to stir at −50° C. for 1 h, then warmed to room temperature. The mixture was diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution, water and brine. After drying (Na₂SO₄), the solution was evaporated to dryness and the residue was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1). The title compound was isolated as a white solid (160 mg, 79%). ¹HNMR (360 MHz, CDCl₃)δ 1.08 (3H, s), 1.11 (3H, s), 2.43 (1H, d, J=18 Hz), 2.53 (1H, d, J=18 Hz), 3.00 (3H, s), 3.03 (2H, s), 7.24-7.28 (1H, m), 7.52-7.54 (1H, m), 7.76-7.80 (1H, m), 8.64-8.66 (1H, m). MS (ES⁺) 320 (M+1).

Step 2: 6,6-Dimethyl-3-((2-hydroxyethyl)thio)-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-methanesulphinyl-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (160 mg, 0.5 mmol) was suspended in ethanol (5 mL) and 4M sodium hydroxide solution (138 μL, 0.55 mmol) was added. 2-Mercaptoethanol (43 mg, 0.55 mmol) was added and the suspension was stirred at 20° C. for 2 h. After this time, further 2-mercaptoethanol (10 mg, 0.12 mmol) and 4M sodium hydroxide solution (35 μL, 0.12 mmol) was added and the mixture stirred for a further 2 h. The mixture was then diluted with ethyl acetate and 1M HCL (1 mL) was added. The ethyl acetate layer was washed with water, dried (Na₂SO₄), then evaporated to dryness. The residue was purified by chromatographed on silica gel, eluting with ethyl acetate, to yield the title compound as a pale yellow solid (58 mg, 36%). mp 175-177° C. Found: C, 61.18; H, 5.62; N, 3.97%. C₁₇H₁₉NO₂S₂ requires: C, 61.26; H, 5.70; N, 4.20%. ¹HNMR (360 MHz, CDCl₃)δ 1.08 (6H, s), 2.45 (2H, s), 2.93 (2H, s), 3.33 (2H, t, J=7.2 Hz), 3.98-4.02 (2H, m), 7.16-7.20 (1H, m), 7.46-7.49 (1H, m), 7.72-7.76 (1H, m), 8.64-8.66 (1H, m). MS (ES⁺) 334 (M+1).

EXAMPLE 37 3-Methylthio-1-(thiazol-2-yl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene Step 1: 1-Cyano-3-methylthio-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene

Cycloheptan-1,3-dione (0.5 g, 4 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (0.48 g of 60% dispersion in oil, 12 mmol) was added and the suspension stirred at 0-5° C. for 30 min. Carbon disulphide (0.45 g, 6 mmol) was added in one portion and the solution was stirred at 0-5° C. for 30 min. Methyl iodide (0.66 g, 4.4 mmol) was added in one portion and the mixture stirred at room temperature for 30 min. After cooling to 0-5° C., bromoacetonitrile (0.27 mL, 4.4 mmol) was added in one portion and the mixture was stirred at room temperature for 30 min. The mixture was then poured into water, extracted with ethyl acetate and the extracts dried (Na₂SO₄). After evaporating to dryness, the residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (1:4) to yield the title compound as a pale yellow solid (280 mg, 32%). ¹HNMR (360 MHz, CDCl₃) δ 1.88-1.96 (4H, m), 2.60 (3H, s), 2.75-2.78 (2H, m), 3.21-3.24 (2H, m). MS (ES⁺) 296 (M+1).

Step 2: 3-Methylthio-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene-1-thiocarboxamide

In the same was as described in Example 6, Step 2, using 1-cyano-3-methylthio-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene, the title compound was isolated as a yellow solid (0.22 g, 68%). ¹HNMR (250 MHz, CDCl₃) δ 1.85-1.90 (4H, m), 2.58 (3H, s), 2.71-2.75 (2H, m), 3.13-3.18 (2H, m). MS (ES⁺) 272 (M+1).

Step 3: 3-Methylthio-1-(thiazol-2-yl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene

In the same way as described in Example 6, Step 3, using 3-methylthio-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophene-1-thiocarboxamide, the title compound was isolated as a pale pink solid (110 mg, 46%). mp 143-145° C. Found: C, 52.85; H, 4.39; N, 4.67%. C₁₃H₁₃NOS₃ requires: C, 52.85; H, 4.44; N, 4.67%. ¹HNMR (360 MHz, CDCl₃) δ 1.88-2.04 (4H, m), 2.60 (3H, s), 2.75-2.78 (2H, m), 3.21-3.24 (2H, m), 7.34 (1H, d, J=3.6 Hz), 7.82 (1H, d, J=3.6 Hz). MS (ES⁺) 296 (M+1).

EXAMPLE 38 6,6-Dimethyl-3-methylthio-1-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid (1.0 g, 3.7 mmol) in dioxan (90 mL) was added carbonyldiimidazole (0.6 g, 3.7 mmol) and the mixture stirred at 20° C. for 30 min. Acetamide oxime (0.41 g, 5.5 mmol) was added and the mixture was heated at 100° C. for 48 h. The solution was evaporated to dryness and the residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (2:3) to yield the title compound as a pale yellow solid (0.1 g, 9%). mp 177-180° C. Found: C, 54.90; H, 5.05; N, 8.71%. C₁₄H₁₆N₂O₂S₂ requires: C, 54.52; H, 5.23; N, 9.08%. ¹HNMR (250 MHz, CDCl₃) δ 1.11 (6H, s), 2.45-2.47 (5H, m), 2.65 (3H, s), 3.11 (2H, s). MS (ES⁺) 309 (M+1).

EXAMPLE 39 6,6-Dimethyl-3-methylthio-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 38, using 2-methylpropionamide oxime, the title compound was isolated as a white solid (990 mg, 80%). mp 172-175° C. Found: C, 56.50; H, 5.94; N, 7.89%. C₁₆H₂₀N₂O₂S₂0.25 (H₂O) requires: C, 57.12; H, 5.99; N, 8.33%. ¹HNMR (250 MHz, CDCl₃) δ 1.10 (6H, s), 1.38 (6H, d, J=7.5 Hz), 2.45 (2H, s), 2.65 (3H, s), 3.10 (2H, s), 3.14 (1H, heptet, J=7.5 Hz). MS (ES⁺) 337 (M+1).

EXAMPLE 40 6,6-Dimethyl-1-(4-benzyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 25, Step 3, using benzylamine, the title compound was isolated as a yellow solid (50 mg, 8%). mp 206-208° C. Found: C, 61.51; H, 5.99; N, 9.68%. C₂₀H₂₁N₃OS₂.0.5 (H₂O) requires: C, 61.20; H, 5.65; N, 10.07%. ¹HNMR (250 MHz, CDCl₃) δ 0.98 (6H, s), 2.40 (2H, s), 2.57 (3H, s), 2.63 (2H, s), 5.26 (2H, s), 7.04-7.12 (2H, m), 7.33-7.35 (3H, m). MS (ES⁺) 384 (M+1).

EXAMPLE 41 6,6-Dimethyl-3-methylthio-1-(1-methyl-1,2,4-triazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboximidic acid ethyl ester (1.0 g, 3.37 mmol) was dissolved in ethanol (60 mL) and methyl hydrazine (0.16 g, 3.37 mmol) was added. The solution was heated at 50° C. for 7 h then evaporated to dryness and the residue was taken up in formic acid (20 mL). The solution was heated at 100° C. for 16 h then evaporated to dryness. The residue was dissolved in CH₂Cl₂ and washed with saturated potassium carbonate solution, then evaporated to dryness. The crude product was purified by chromatographed on silica gel, eluting with ethyl acetate to yield the title compound as a yellow solid (0.15 g, 15%). mp 146-148° C. Found: C, 54.55; H, 5.46; N, 13.27%. C₁₄H₁₇N₃OS₂ requires; C,54.70; H, 5.77; N, 13.27%. ¹HNMR (250 MHz, CDCl₃) δ 1.05 (6H, s), 2.44 (2H, s), 2.63 (3H, s), 2.74 (2H, s), 3.96 (3H, s), 7.98 (1H, s). MS (ES⁺) 308 (M+1).

EXAMPLE 42 6,6-Dimethyl-3-methylthio-1-(oxazolidin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-caboximidic acid ethyl ester (0.3 g, 0.89 mmol) in ethanol (20 mL) was added ethanolamine (0.06 g, 0.8 mmol) and diisopropylethylamine (0.23 g, 1.8 mmol). The mixture was heated at 60° C. for 8 h, then the solvent was removed in vacuo. The residue was triturated with ethyl acetate and the solid product collected by filtration, to yield the title compound as a colourless solid (50 mg, 19%). mp 190-193° C. Found: C, 56.97; H, 5.51; N, 4.75%. C₁₄H₁₇NO₂S₂ requires: C, 56.92; H, 5.80; N, 4.74%. ¹HNMR (250 MHz, CDCl₃), δ 1.06 (6H, s), 2.40 (2H, s), 2.60 (3H, s), 3.01 (2H, s), 4.04 (2H, t, J=10 Hz), 4.42 (2H, t, J=10 Hz). MS (ES⁺) 296 (M+1).

EXAMPLE 43 3-Methylthio-1-(oxazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In a similar way to that in Example 35, using 1-bromo-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 2-(tri-n-butylstannyl)oxazole, the title compound was isolated as a pale yellow solid (35 mg, 37%). mp 157-159° C. Found: C, 54.0; H, 3.7; N, 5.6%. C₁₂H₁₁NO₂S₂ requires: C, 54.32; H, 4.18; N, 5.28%. ¹HNMR (250 MHz, CDCl₃) δ 2.05-2.16 (2H, m), 2.56-2.61 (2H, m), 2.63 (3H, s), 3.20-3.25 (2H, m), 7.20 (1H, s), 7.66 (1H, s). MS (ES⁺) 266 (M+1).

EXAMPLE 44 6,6-Dimethyl-3-methylthio-1-(pyrazin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 35, using 2-(tri-n-butylstannyl)pyrazine, the title compound was isolated as a pale yellow solid (90 mg, 30%). mp 208-210° C. Found: C, 58.53; H, 5.11; N, 8.38%. C₁₅H₁₆N₂OS₂.0.3 (H₂O) requires: C, 58.15; H, 5.40; N, 8.78%. ¹HNMR (250 MHz, CDCl₃) δ 1.10 (6H, s), 2.46 (2H, s), 2.66 (3H, s), 2.98 (2H, s), 8.43 (1H, d, J=2.5 Hz), 8.56 (1H, d, J=2.5 Hz), 8.81 (1H, s). MS (ES⁺) 305 (M+1).

EXAMPLE 45 6,6-Dimethyl-3-methylthio-1-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 33, Step 1, using pyrimidin-5-yl boronic acid, the title compound was isolated as a pale yellow solid (10 mg, 7%). mp 158-161° C. Found: C, 55.56; H, 4.59; N, 7.78%. C₁₅H₁₆N₂OS₂.1.2 (H₂O) requires: C, 55.26; H, 5.01; N, 8.05 %. ¹HNMR (250 MHz, CDCl₃) δ 1.05 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.76 (2H, s), 8.81 (2H, s). 9.17 (1H, s). MS (ES⁺) 305 ((M+1).

EXAMPLE 46 6,6-Dimethyl-1-(imidazolin-2yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same was as described in Example 42, using 1,2-diaminoethane, the title compound was isolated as a white solid (90 mg, 70%). mp 172-175° C. Found: C, 43.76; H, 4.93; N, 6.85%. C₁₄H₁₈N₂OS₂.2HCl.H₂O requires: C, 43.64; H, 5.25; N, 7.27%. ¹HNMR (250 MHz, CDCl₃) δ 1.08 (6H, s), 2.42 (2H, s), 2.63 (3H, s), 2.92 (2H, s), 3.83 (4H, s). MS (ES⁺) 295 (M+1).

EXAMPLE 47 3-Methylthio-6,6-spirocyclohexyl-1-(thiazol-2yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 1-Cyano-3-methylthio-6,6-spirocyclohexyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 37, Step 1, using 5,5-spirocyclohexyl cyclohexane-1,3-dione, the title compound was isolated as a yellow solid (0.27 g, 33%). ¹HNMR (250 MHz, CDCl₃) δ 1.18-1.47 (10H, m), 2.49 (2H, s), 2.62 (3H, s), 2.87 (2H, s).

Step 2: 3-Methylthio-6,6-spirocyclohexyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide

In the same way as described in Example 37, Step 2, using 1-cyano-3-methylthio-6,6-spirocyclohexyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound was isolated as a yellow solid (0.29 g, 100%). ¹HNMR (250 MHz, CDCl₃) δ 1.40-1.60 (10H, m), 2.50 (2H, s), 2.63 (3H, s), 2.95 (2H, s). MS (ES⁻) 326 (M+1).

Step 3: 3-Methylthio-6,6-spirocyclohexyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 37, Step 3, using 3-methylthio-6,6-spirocyclohexyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-thiocarboxamide, the title compound was isolated as cream-coloured solid (130 mg, 41%). mp 164-167° C. Found: C, 58.11; H, 5.37; N, 3.94%. C₁₇H₁₉NOS₃ requires: C, 58.42; H, 5.48; N, 4.01%. ¹HNMR (250 MHz, CDCl₃) δ 1.40-1.60 (10H, m), 2.53 (2H, s), 2.64 (3H, s), 2.95 (2H, s), 7.35 (1H, d, J=3.3 Hz), 7.82 (1H, d, J=3.3 Hz). MS (ES⁺) 350 (M+1).

EXAMPLE 48 6,6-Dimethyl-1-(3-(N-methylaminocarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (100 mg, 0.26 mmol) and methylamine (5 mL of a 33% (w/v) solution in ethanol) was stirred for 3h. After this time the solvent was evaporated and the solid triturated with ether. The title compound (65 mg, 69%) was isolated as a pale yellow solid. mp 202-204° C. ¹HNMR (360 MHz, CDCl₃) δ 1.13 (6H, s), 2.47 (2H, s), 2.66 (3H, s), 2.87 (2H, s), 3.05 (2H, d, J=5.2 Hz), 8.08 (1H, s). MS (ES⁺) 367 (M+1).

EXAMPLE 49 6,6-Dimethyl-3-methylthio-1-(thiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as described in Example 35, using 5-(tri-n-butylstannyl)thiazole and dichlorobistriphenylphosphine palladium, the title compound (20 mg, 20% was isolated as a yellow solid. mp 138-140° C. ¹ HNMR (250 MHz, CDCl₃) δ 1.07 (6H, s), 2.44 (2H, s), 2.62 (3H, s), 2.75 (2H, s), 7.90 (1H, s), 8.80 (1H, s). MS (ES⁺) 310 (M+1).

EXAMPLE 50 6,6-Dimethyl-3-tert-butylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

A solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (100 mg, 0.33 mmol) and tert-butylamine (0.69 mL, 6.6 mmol) in butanol (6 mL) was heated at 150° C., in a sealed tube, for 5 days. After this time the solvent was removed in vacuo and the residue partitioned between EtOAc (20 mL) and water (2×20 mL). The organic layer was separated, dried (MgSO₄) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (2:1), to give the title compound (9 mg, 9%) as a beige solid. mp 260-262° C. ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6H, s), 1.48 (9H, s), 2.33 (2H, s), 2.71 (2H, s), 6.41 (1H, d, J=2.3 Hz), 7.59 (1H, d, J=2.3 Hz), 9.47 (1H, br, s). MS (ES⁺). 318 (M+1).

EXAMPLE 51 3-Cyclobutoxy-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (178 mg, 0.59 mmol) in cyclobutanol (1 mL) and THF (3 mL) was added sodium hydride (70 mg of a 60% dispersion in oil, 1.76 mmol). After effervescence had ceased the mixture was heated at 95° C. for 2h before the solvent was evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1) to give the title compound (22 mg, 12%) as a pale yellow solid. mp 202-204° C. Found: C, 62.48; H, 6.24; N, 8.49%. C₁₇H₂₀N₂O₂S .0.5(H₂O) requires: C, 62.74; H, 6.50; N, 8.61% ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6H, s), 1.60-1.76 (1H, m), 1.86-1.97 (1H, m), 2.37 (2H, s), 2.38-2.47 (2H, m), 2.50-2.60 (2H, m), 2.79 (2H, s), 4.76 (1H, pentet, J=7.2 Hz), 6.45 (1H, d, J=2.4 Hz), 7.62 (1H, d, J=2.4 Hz). MS (ES⁺) 317 (M+1).

EXAMPLE 52 6,6-Dimethyl-1-[(3-ethoxycarbonyl)isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as that described in Example 35 using 1-bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, 2-(tri-n-butylstannyl)pyridine and dichlorobistriphenylphosphine palladium (II), the title compound (10 mg, 7%) was isolated as a solid. mp 178-179° C. ¹H NMR (250 MHz, CDCl₃) δ 1.10 (6H, s), 1.45 (3H, t, J=7.1 Hz), 2.46 (2H, s), 2.65 (3H, s), 2.87 (2H, s), 4.48 (2H, q, J=7.1 Hz), 6.68 (1H, s). MS (ES⁺) 366 (M+1).

EXAMPLE 53 6,6-Dimethyl-3-phenoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a solution of phenol (116 mg, 1.1 mmol) in THF (10 mL) was added 6,6-dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (0.2 g, 0.62 mmol) and NaOH (0.3 mL of a 4M solution, 1.1 mmol). The mixture was heated at reflux overnight. Phenol (50 mg, 0.62 mmol) and NaOH (0.15 mL of a 4M solution, 0.62 mmol) were then added and the mixture heated at reflux for an additional 8 h. The solution was cooled to room temperature, diluted with EtOAc (100 mL) and washed with NaOH (1M, 2×100 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was chromatographed on silica gel, eluting with hexane:EtOAc (2:1) to give the title compound (35 mg, 18%) as a yellow solid. mp 232-234° C. ¹H NMR (360 MHz, CDCl₃) δ 1.10 (6H, s), 2.42 (2H, s), 2.86 (2H, s), 6.43 (1H, d, J=2.3 Hz), 7.20-7.26 (3H, m), 7.37 (1H, d, J=7.3 Hz), 7.39 (1H, d, J=8.7 Hz), 7.59 (1H, d, J=2.3 Hz). MS (ES⁺) 339 (M+1).

The following process was used to prepare Examples 54-92.

To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (50 mg, 0.15 mmol) in EtOH (2 mL) was added NaOH (77 μL of a 4M solution, 0.31 mmol) followed by the appropriate thiol (0.31 mmol). The mixture was then stirred at room temperature for 90 min or at 70° C. for 3-72 h. The mixture was then diluted with MeOH:H₂O:1MHCl (5:5:1) and poured onto a C-18 Bond Elut cartridge (prewashed with MeOH followed by water). The cartridge was eluted with MeOH:H₂O (8 mL) (1:1→1:0) and the product fractions evaporated. The residue was triturated with Et₂O to give the appropriate thioether as a solid.

EXAMPLE 54 6,6-Dimethyl-3-pentylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4one

mp. 121-123° C. ¹H NMR (360 MHz, CDCl₃) δ 0.92 (3H, t, J=7.2 Hz). 1.07 (6H, s), 1.18-1.50 (4H, m), 1.84 (2H, pentet, J=7.5 Hz), 2.43 (2H, s), 2.85 (2H, s), 3.07 (2H, t, J=7.3 Hz), 6.48 (1H, d, J=2.3 Hz), 7.64 (1H, d, J=2.3 Hz). MS (ES⁻) 349 (M+1).

EXAMPLE 55 3-Butylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 149-150° C. Found: C, 60.96; H, 6.43; N 8.43%. C₁₇H₂₂N₂OS₂ requires: C, 61.04; H, 6.63; N, 8.37%. ¹H NMR (360 MHz, CDCl₃) δ 0.96 (3H, t, J=7.4 Hz), 1.07 (6H, s), 1.52 (2H, sextet, J=7.4 Hz), 1.82 (2H, pentet, J=7.6 Hz), 2.43 (2H, s), 2.85 (2H, s), 3.08 (2H, t, J=7.4 Hz), 6.48 (1H, d, J=2.3 Hz), 7.64 (1H, d, J=2.3 Hz). MS (ES⁺) 335 (M+1).

EXAMPLE 56 3-[(3-Chloropropyl)thio]-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 150-151° C. Found: C, 54.29; H, 5.43; N, 7.83%. C₁₆H₁₉ClN₂OS₂ requires: C, 54.15; H, 5.40; N, 7.89%. ¹H NMR (360 MHz, CDCl₃) δ 1.08 (6H, s), 2.30 (2H, pentet, J=6.7 Hz), 2.43 (2H, s), 2.86 (2H, s), 3.24 (2H, t, J=7.1 Hz), 3.71 (2H, t, J=6.4 Hz), 6.49 (1H, d, J=2.3 Hz), 7.64 (1H, d, J=2.3 Hz). MS (ES⁺) 355/357 (M+1).

EXAMPLE 57 6,6-Dimethyl-3-((2-phenylethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 173-175° C. Found: C, 65.64; H, 5.64; N, 7.09%. C₂₁H₂₂N₂OS₂ requires: C, 65.94; H, 5.80; N, 7.32%. ¹H NMR (360 MHz, CDCl₃) δ 1.08 (6H, s), 2.43 (2H, s), 2.86 (2H, s), 3.12 (2H, t, J=8.5 Hz), 3.33 (2H, t, J=8.5 Hz), 6.49 (1H, d, J=2.3 Hz), 7.25-7.32 (5H, m), 7.64 (1H, d, J=2.3 Hz). MS (ES⁺) 383 (M+1).

EXAMPLE 58 6,6-Diemthyl-3-propylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 181-182° C. Found: C, 59.90; H, 5.99; N, 8.64%. C₁₆H₂₀N₂OS₂ requires: C, 59.97; H, 6.29; N, 8.74%. ¹H NMR (360 MHz. CDCl₃) δ1.07, (6H, s), 1.10 (3H, t, J=7.3 Hz), 2.43 (2H, s), 2.85 (2H, s), 3.05 (2H, t, J=7.3 Hz), 6.48 (1H, d, J=2.3 Hz), 7.64 (1H, d, J=2.3 Hz). MS (ES⁺) 321 (M+1).

EXAMPLE 59 6,6-Dimethyl-3-((2-methylbutyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 158-159° C. Found: C, 62.06; H, 6.86; N, 8.03%. C₁−H₂₄N₂OS₂ requires: C,62.03; H, 6.94; N, 8.04%. ¹H NMR (360 MHz. CDCl₃) δ0.95% (3H, t. J=7.4 Hz), 1.07 (6H, s), 1.30-1.40 (1H, m). 1.58-1.68 (1H. m), 1.83-1.94 (1H. m). 2.43 (2H, s). 2.84 (2H, s), 290-2.98 (1H, m). 3.07-3.12 (1H. m). 6.48 (1H, d, J=2.3 Hz), 7.64 (1H, d, J=2.3 Hz). MS (ES³⁴ ) 349 )M+1).

EXAMPLE 60 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((2,2,2-trifluoroethyl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 141-142° C. Found: C, 50.02; H, 3.98: N, 7.84%, C₁₇H₁₅F₃N₂OS₂ requires: C, 49.99; H, 4.20; N, 7.77% ¹H NMR (360 MHz. CDCl₃) δ1.08 (6H. s), 2.45 (2H. s). 2.88 (2H, s). 3.69 (2H. q, J=9.6 Hz). 6.50 (1H. d. J=2.3 Hz), 7.65 (1H. d. J=2.3 Hz). MS (ES⁺) (M+1).

EXAMPLE 61 6,6-Dimethyl-3-((1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 151-152° C. Found: C, 61.30; H, 6.64; N, 8.36%. C₁₇H₂₂N₂OS₂ requires: C, 61.04; H, 6.63; N, 8.37%. ¹H NMR (360 MHz, CDCl₃) δ1.04-1.09 (9H, m), 1.49 (3H, d, J=6.7 Hz), 1.69-1.78 (1H, m), 1.83-1.92 (1H, m), 2.43 (2H, s), 2.84 (2H, s), 3.36 (1H, sextet, J=6.6 Hz), 6.48 (1H, d, J=2.3 Hz), 7.65 (1H, d, J=2.3 Hz). MS (ES⁺) 335 (M+1).

EXAMPLE 62 3-((4-Chlorophenyl)thio)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 186-187° C. ¹H NMR (360 MHz, CDCl₃) δ1.09 (6H, s), 2.46 (2H, s), 2.84 (2H, s), 6.40 (1H, d, J=2.3 Hz), 7.42 (2H, d, J=8.5 Hz). 7.58 (1H. d. J=2.3 Hz), 7.64 (2H, d, J=8.5 Hz). MS (ES⁺) 389 (M+1).

EXAMPLE 63 6,6-Dimethyl-3-((3-fluorophenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 264-266° C. Found: C. 60.39: H, 4.35: N, 7.33%. C₁₉H₁₇FN₂OS₂ .0.3(H₂O) requires: C. 60.39: H. 4.69; N. 7.41%. ¹H NMR (360 MHz. CDCl₃) δ1.10 (6H, s), 2.84 (2H, s), 2.84 (2H. s). 6.41 (1H. d. J=2.3 Hz). 7.16-7.22 (1H. m). 7.40-7.46 (2H, m). 7.48-7.52 (1H. m). 7.58 (1H. d, J=2.3 Hz). MS (ES⁻) 373 (M+1).

EXAMPLE 64 3-((4-Acetylaminophenyl)thio)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 236-237° C. Found: C, 61.06; H, 4.87; N, 10.54%. C₂₁H₂₁N₃O₃S₂ requires: C, 61.29; H, 5.14; N, 10.21%. ¹H NMR (360 MHz, CDCl₃) δ1.09 (6H, s), 2.21 (3H, s), 2.46 (2H, s), 2.83 (2H, s), 6.39 (1H, s), 7.26 (1H, br s). 7.50-7.70 (5H, m). MS (ES⁺) 412 (M+1).

EXAMPLE 65 6,6-dimethyl-3-((4-methoxyphenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 227-229° C. Found: C, 62.13; H, 5.03; N, 7.18%. C₂₀H₂₀N₂O₂S₂ requires: C, 62.47; H, 5.24; N, 7.29%. ¹H NMR (360 MHz, CDCl₃) δ1.09 (6H. s). 2.46 (2H, s), 2.82 (2H. s), 3.86 (3H, s), 6.39 (1H, d, J=2.4 Hz), 6.96 (2H. d. J=8.8 Hz), 7.56 (1H, d, J=2.4 Hz), 7.61 (2H. d. J=8.8 Hz). MS (ES^(÷)) 385 (M+1).

EXAMPLE 66 6,6-Dimethyl-3-((1-methylimidazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

¹H NMR (360 MHz, CDCl₃+d⁴⁻MeOH) δ1.09 (6H. s). 2.47 (2H. s), 2.83 (2H. s). 3.80 (3H. s). 6.39 (1H, d, J=3.3 Hz). 7.22 (1H. s). 7.24 (1H. s). 7.59 (1H. d. J=3.4 Hz). MS (ES⁺) 359 (M+1).

EXAMPLE 67 6,6-Dimethyl-3-((thiophen-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 226-228° C. Found: C, 56.16; H, 4.27; N, 7.55%. C₁₇H₁₆N₂OS₃ .0.15(H₂O) requires: C, 56.22; H, 4.52; N, 7.71%. ¹H NMR (360 MHz, CDCl₃) δ1.09 (6H, s), 2.46 (2H, s), 2.83 (2H, s), 6.40 (1H, d, J=2.3 Hz), 7.13 (1H, dd, J=5.3 and 3.6 Hz), 7.43 (1H, d, J=3.6 Hz), 7.57-7.61 (2H, m). MS (ES⁺) 361 (M+1).

EXAMPLE 68 6,6-Dimethyl-3-((imidazol-2-yl)thio)-1-(pyrazol-3yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 242-245° C. Found: C, 54.99; H, 4.70; N, 15.59%. C₁₆H₁₆N₄OS₂ .0.4(H₂O) requires: C, 54.65; H, 4.82; N, 15.93%. ¹H NMR (360 MHz, CDCl₃+d⁴⁻MeOH) δ1.07 (6H, s), 2.45 (2H, s), 2.80 (2H, s). 6.37 (1H, d, J=2.4 Hz), 7.22 (2H, br s), 7.57 (1H, d, J=2.4 Hz). MS (ES⁺) 345 (M+1).

EXAMPLE 69 6,6-Dimethyl-3-((4-phenylthiazol-2-yl)-2-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 227-228° C. Found: C, 60.44; H, 4.30; N, 9.32%. C₂₂H₁₉N₃OS₃ requires: C. 60.39: H. 4.38: N, 9.60%. ¹H NMR (360 MHz. CDCl₃) δ1.00 (6H. s). 2.39 (2H. s), 2.78 (2H, s). 6.34 (1H, d. J=2.3 Hz). 7.16-7.36 (3H. m). 7.49 (1H. d. J=2.3 Hz). 7.54 (1H. s). 7.85-7.88 (2H. m). MS (ES⁻) 438 (M+1).

EXAMPLE 70 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((1,2,4-triazol-3-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 182-184° C. ¹H NMR (360 MHz, CDCl₃+d⁴⁻MeOH) δ1.08 (6H, s). 2.46 (2H, s), 2.82 (2H, s), 6.40 (1H, d, J=2.2 Hz), 7.58 (1H, d, J=2.2 Hz), 8.33 (1H, s). MS (ES⁺) 346 (M+1).

EXAMPLE 71 6,6-Dimethyl-3-((5-methyl-1,3,4-thiadiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 170-172° C. ¹H NMR (360 MHz, CDCl₃) δ1.10 (6H, s), 2.48 (2H. s), 2.82 (3H, s), 2.90 (2H, s), 6.48 (1H, d, J=2.3 Hz), 7.63 (1H, d. J=2.3 Hz). MS (ES⁺) 377 (M+1).

EXAMPLE 72 6,6-Dimethyl-3-((4-methyl-1,2,4-triazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 234-236° C. ¹H NMR (360 MHz. CDCl₃+d⁴⁻MeOH) δ1.10 (6H. s). 2.48 (2H, s), 2.84 (2H, s). 3.79 (3H, s), 6.40 (1H, d. J=2.1 Hz). 7.59 (1H. d. J=2.1 Hz). 8.47 (1H, s). MS (ES⁺) 360 (M+1).

EXAMPLE 73 6,6-Dimethyl-3-((5-methylthio-1,3,4-thiadiazol-2-yl)thio)-1-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp. 192-194° C. ¹H NMR (360 MHz, CDCl₃) δ1.09 (6H, s), 2.48 (2H, s), 2.82 (3H, s), 2.88 (2H, s), 6.45 (1H, d, J=2.4 Hz), 7.61 (1H, d, J=2.4 Hz). MS (ES⁺) 409 (M+1).

EXAMPLE 74 3-Benzylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 215-218° C. Found: C, 62.83; H, 5.47; N, 7.03%. C₂₀H₂₀N₂OS₂.0.8 (H₂O) requires: C, 62.73; H, 5.69; N, 7.32%.

¹H NMR (360 MHz, d⁶⁻DMSO) δ0.99 (6H, s), 2.37 (2H, s), 2.83 (2H, s), 4.34 (2H, s), 6.47-6.49 (1H, m), 7.27-7.31 (1H, m), 7.34-7.38 (1H, m), 7.46-7.49 (1H, m), 7.83-7.85 (1H, m). 13.00 (1H, br s). MS (ES⁺) 369 (M+1).

EXAMPLE 75 3-Cyclopenthylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 212-214° C. Found: C, 61.36; H, 6.27; N, 7.78%. C₁₈H₂₂N₂OS₂.0.4 (H₂O) requires: C. 61.12: H. 6.50; N. 7.92%.

¹H NMR (360 MHz. d⁶⁻DMSO) δ0.99 (6H, s), 1.60-1.80 (6H. m), 2.20-2.30 (2H. m). 2.36 (2H, s). 2.83 (2H, s), 3.66-3.72 (1H. m). 6.49 (1H. d. J=2.3 Hz). 7.84 (1H. br s). 13.02 (1H. br s). MS (ES⁺) 346 (M+1).

EXAMPLE 76 6,6-Dimethyl-3-((2-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 186-188° C.

¹H NMR (360 MHz, d₆DMSO) δ0.99 (6H, s), 1.05 (6H, d, J=6.6 Hz), 1.98-2.08 (1H, m), 2.37 (2H, s), 2.84 (2H, s), 2.95 (2H, d, J=6.8 Hz). 6.49 (1H, d, J=2.2 Hz), 7.84 (1H, br s), 13.00 (1H, br s). MS (ES⁺) 335 (M+1).

EXAMPLE 77 6,6-Dimethyl-3-hexylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 134-137° C. Found: C, 62.27; H, 7.28; N, 7.35%. C₁₉H₂₆N₂OS₂.0.25 (H₂O) requires: C, 62.17; H, 7.28; N, 7.63%.

¹H NMR (360 MHz, d⁶⁻DMSO) δ0.85-0.90 (3H, m), 1.00 (6H. s), 1.26-1.34 (4H. m), 1.40-1.50 (2H, m), 1.60-1.78 (2H, m), 2.37 (2H, s). 2.84 (2H. s). 3.05 (2H, t, J=7.2 Hz), 6.48-6.50 (1H, m), 7.82-7.86 (1H, m), 13.00 (1H, br s). MS (ES⁺) 363 )(M+1).

EXAMPLE 78 6,6-Dimethyl-3-isopropylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 195-198° C. Found: C, 59.29: H, 6.00: N, 8.31%. C₁₆H₂₀N₂OS₂.0.2 (H₂O) requires: C. 59.30: H. 6.35: N, 8.64%.

¹H NMR (360 MHz, d⁶⁻DMSO) δ0.99 (6H, s), 1.42 (6H, d, J=6.7 Hz). 2.37 (2H, s), 2.84 (2H, s), 3.50-3.58 (1H, m), 6.50 (1H, d, J=2.2 Hz), 7.85 (1H, br s), 13.02 (1H, br s). MS (ES⁺) 320 )M+1).

EXAMPLE 79 6,6-Dimethyl-3-((furan-2-ylmethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 198-200° C. Found: C, 58.91; H, 490; N, 7.39%. C₁₈H₁₈N₂O₂S₂.0.5 (H₂O) requires: C, 58.83; H, 4.90; N, 7.62%.

¹H NMR (360 MHz, D⁶⁻DMSO) δ0.99 (6H, s), 2.38 (2H, s), 2.84 (2H, s), 4.40 (2H, s), 6.40-6.45 (2H, m), 6.48-6.52 (1H, m), 7.63 (1H, s), 7.85 (1H, br s). 13.02 (1H, br s). MS (ES⁺) 359 (M+1).

EXAMPLE 80 6,6-Dimethyl-3-((2-hydroxy-1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 171-174° C. Found: C, 56.86; H. 6.12; N, 7.64%. C₁₇H₂₂N₂O₂S₂.0.5 (H₂O) requires: C, 56.80; H, 6.45; N, 7.79%.

¹H NMR (360 MHz, d⁶⁻DMSO) δ0.98-1.00 (6H, m). 1.14-1.19 (3H. m), 1.36-1.40 (3H, m). 2.37 (2H, s), 2.83 (2H. s). 3.30-3.44 (1H. m), 3.90-3.98 (1H. m). 5.03 and 5.12 (1H. 2xd, J=5.2 Hz), 6.49 (1H. br s). 7.84 (1H. br s). 13.00 (1H, br s). MS (ES⁺) 351 (M+1).

EXAMPLE 81 6,6-Dimethyl-3-((2,3-dihydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 70° C.

¹H NMR (360 MHz, d₆-DMSO) δ 1.00 (6H, s), 2,37 (2H, s), 3.01 (1H, dd, J=12.1 and 7.7 Hz), 3.25 (1H, dd, J=12.2 and 4.3 Hz), 3.38 (1H, dd, J=11.1 and 5.9 Hz), 3.45-351 (3H, m). 6.48 (1H, d, J=2.3 Hz), 7.82 (1H, d, J=2.3 Hz). MS (ES⁺) 353 (M+1).

EXAMPLE 82 6,6-Dimethyl-3-((2-hydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 175-178° C. Found: C, 53.03; H, 6.12; N, 7.57%. C₁₆H₂₀N₂O₂S₂.1.4 (H₂O) requires: C, 53.13; H, 6.35; N, 7.75%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.99 (3H, s), 1.00 (3H, s), 1.21 (3H, d, J=6.2 Hz), 2.37 (2H, s), 3.07 (2H, d, J=5.9 Hz), 3.97 (1H, q, J=6.1 Hz), 6.49 (1H, d, J=2.3 Hz), 7.83 (1H, br s). MS (ES⁺) 337 (M+1).

EXAMPLE 83 6,6-Dimethyl-3-(((N-methylaminocarbonyl)methyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 180° C.

¹H NMR (360 MHz, d₆-DMSO) δ 1.00 (6H, s), 2.38 (2H, s), 2.60-2.64 (3H, m), 2.83 (2H, s), 3.99 (2H, s), 6.48 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=2.4 Hz), 8.20-8.28 (1H, m). MS (ES⁺) 350 (M+1).

EXAMPLE 84 6.6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-4-yl)thio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 190° C. Found: C, 58.44; H, 4.65; N, 10.98%. C₁₈H₁₇N₃OS₂.0.75 (H₂O) requires: C, 58.59; H, 5.05; N, 11.39%.

¹NMR (360 MHz, d₆-DMSO) δ 1.03 (6H, s), 2.45 (2H, s), 2.90 (2H, s), 6.53 (1H, d, J=2.3 Hz), 7.50-7.52 (2H, m), 7.84 (1H, d, J=2.3 Hz), 8.58-8.60 (2H, m). MS (ES⁺) 356 (M+1).

EXAMPLE 85 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrimidin-2-yl)thio)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 245° C. Found: C, 56.64; H, 4.40; N, 15.07%. C₁₇H₁₆N₄OS₂.0.5 (H₂O) requires: C, 55.87; H, 4.69; N, 15.33%.

¹H NMR (360 MHz, d₆-DMSO) δ 1.03 (6H, s), 2.45 (2H, s), 2.91 (2H, s), 6.56 (1H, d, J=2.3 Hz), 7.39 (1H, t, J=4.9 Hz), 7.88 (1H, br s), 8.78 (2H, d, J=4.9 Hz), 13.08 (1H, br s). MS (ES³⁰) 357 (M+1).

EXAMPLE 86 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((thiazol-2-yl)thio)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 195-198° C. Found: C, 52.89; H, 3.82; N, 11.30%. C₁₆H₁₅N₄OS, requires: C, 53.16; H, 4.18: N, 11.62%.

¹H NMR (360 MHz, d₆-DMSO) δ 1.03 (6H, s), 2.47 (2H, s), 2.87 (2H, s), 6.48-6.50 (1H, m), 7.83-7.85 (1H, m), 8.04-8.08 (2H, m), 13.03 (1H, br s). MS (ES⁺) 362 (M+1).

EXAMPLE 87 6,6-Dimethyl-3-(prop-2-enylthio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 164-167° C. Found: C, 59.80; H, 5.67; N, 8.43%. C₁₆H₁₈N₂OS₂.0.1 (H₂O) requires: C, 60.10; H, 5.73; N, .875%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 2.43 (2H, s), 2.85 (2H, s), 3.71-3.75 (2H, m), 5.23-5.27 (1H, m), 5.83-5.44 (1H, m), 5.93-6.05 (1H, m), 6.48 (1H, d, J=2.5 Hz), 7.65 (1H, d, J=2.4 Hz). MS (ES⁺) 319 (M+1).

EXAMPLE 88 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-2-yl)thio)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 207-209° C. Found: C, 60.75; H, 4.69; N, 11.49%. C₁₈H₁₇N₃OS₂ requires: C, 60.82; H, 4.82; N, 11.82%. ¹H NMR (360 MHz, CDCl₃) δ 1.09 (6H, s), 2.47 (2H, s), 2.89 (2H, s), 6.49 (1H, d, J=2.3 Hz), 7.19-7.23 (1H, m), 7.50 (1H, d, J=8.0 Hz), 7.63-7.69 (2H, m), 8.60-8.64 (1H, m). MS (ES⁺) 356 (M+1).

EXAMPLE 89 6,6-Dimethyl-3-ethylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 182-184° C. Found: C, 58.41; H, 5.79; N, 8.95%. C₁₅H₁₈N₂OS₂ requires: C, 58.79; H, 5.92; N, 9.14%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 1.48 (3H, t, J=7.4 Hz), 2.43 (2H, s), 2.85 (2H, s), 3.10 (2H, q, J=7.3 Hz), 6.49 (1H, br s), 7.65 (1H, d, J=2.3 Hz). MS (ES⁺) 307 (M+1).

EXAMPLE 90 6,6-Dimethyl-3-phenylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 231-234° C. Found: C, 62.36; H, 5.07; N, 7.46%. C₁₉H₁₈OS₂.0.6 (H₂O) requires: C, 62.47; H, 5.30; N, 7.67%. ¹H NMR (360 MHz, CDCl₃) δ 1.09 (6H, s), 2.47 (2H, s), 2.83 (2H, s), 6.38 (1H, br s), 7.43-7.47 (3H, m), 7.55 (1H, d, J=2.3 Hz), 7.69-7.73 (2H, m). MS (ES⁺) 355 (M+1).

EXAMPLE 91 6,6-Dimethyl-3-((N,N-dimethyl-2-aminoethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 212-214° C. Found: C, 58.03; H, 6.41; N, 11.58%. C₁₇H₂₃N₃OS₂.0.1 (H₂O) requires: C, 58.12; H, 6.66; N, 11.96%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 2.32 (6H, s), 2.42 (2H, s), 2.75 (2H, t, J=7.6 Hz), 2.85 (2H, s), 3.20 (2H, t, J=7.5 Hz), 6.47 (1H, d, J=2.5 Hz), 7.63 (1H, d, J=2.5 Hz). MS (ES⁺) 350 (M+1).

EXAMPLE 92 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 182-185° C. Found: C, 54.74; H, 5.74; N, 8.22%. C₁₅H₁₈N₂O₂S₂.0.4 (H₂O) requires: C, 54.65; H, 5.75; N, 8.50%. ¹H NMR (360 MHz, d₆-DMSO) δ 1.00 (6H, s) 2.37 (2H, s), 2.83 (2H, s), 3.16 (2H, t, J=9.2 Hz), 3.70-3.80 (2H, m), 5.14 (1H, br m), 6.49 (1H, d, J=3.3 Hz), 7.84 (1H, br s), 13.04 (1H, br s). MS (ES⁺) 323 (M+1).

EXAMPLE 93 6,6-Dimethyl-3-[(2-hydroxypropyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 172-175° C. Found: C, 56.96; H, 5.88; N, 8.34%. C₁₆H₂₀N₂O₂S₂ requires: C, 57.11; H, 5.99; N, 8.33%. ¹H NMR (360 MHz, d₆-DMSO) δ 1.00 (6H, s), 1.83-1.92 (2H, m), 2.37 (2H, s), 2.84 (2H, s), 3.09 (2H, t, J=7.2 Hz), 3.51-3.56 (2H, m), 4.66 (1H, t, J=5.3 Hz), 6.49 (1H, br s), 7.84 (1H, br s), 13.00 (1H, br s). MS (ES⁺) 337 (M+1).

EXAMPLE 94 6,6-Dimethyl-3-[(2-methoxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp. 159-162° C. Found: C, 56.64; H, 5.80; N, 8.44%. C₁₀H₂₀N₂O₂S₂.0.2 (H₂O) requires: C, 56.51; H, 6.05; N, 8.24%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6H, s), 2.43 (2H, s), 2.85 (2H, s), 3.29 (2H, t, J=6.5 Hz), 3.41 (3H, s), 3.77 (2H, t, J=6.6 Hz), 6.49 (2H, d, J=2.2 Hz), 7.66 (2H, d, J=2.4 Hz). MS (ES⁺) 337 (M+1).

EXAMPLE 95 6,6-Dimethyl-1-(isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one Step 1: 6,6-Dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

To a suspension of sodium hydride (149 mg of a 60% dispersion in oil. 3.7 mmol) in THF (7 mL) was added ethyl formate (0.75 mL, 9.3 mmol) at 0° C., under nitrogen. After addition a solution of 1-acetyl-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (0.5 g, 1.9 mmol) in THF (7 mL) was added. The mixture was stirred overnight at room temperature. Methanol (0.5 mL) and water (0.5 mL) were then added to the mixture and the solvent removed in vacuo. The residue was dissolved in water and acidified using 1M HCl. The resultant solid was collected by filtration then partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated, dried (Na₂SO₄) and evaporated. The residue was triturated with ether and the title compound (0.4 g, 80%) was isolated as a yellow solid. ¹H NMR (360 MHz, CDCl₃) δ 1.09 (6H, s), 2.43 (2H, s), 2.63 (3H, s), 3.08 (2H, s), 5.85 (1H, d, J=5.1 Hz), 7.77 (1H, d, J=5.1 Hz), 14.90 (1H, br s). MS (ES⁺) 297 (M+1).

Step 2: 6,6-Dimethyl-1-(isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

A solution of 6,6-dimethyl-1-(3-hydroxy-1-oxoprop-2-enyl)-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (200 mg, 0.68 mmol) in ethanol (14 mL) and water (1.6 mL) was heated to 80° C., after which hydroxylamine hydrochloride (52 mg, 0.74 mmol) was added. The mixture was heated at reflux for 4 h, after which time the solvent was removed in vacuo and the residue triturated in hexane/ether. The isoxazole (50 mg, 20%) was isolated as a colourless solid. mp 143-145° C. ¹H NMR (360 MHz, CDCl₃) δ 1.09 (6H, s), 2.45 (2H, s), 2.64 (3H, s), 2.90 (2H, s), 6.28 (1H, d, J=1.9 Hz), 8.29 (1H, d, J=1.9 Hz). MS (ES⁺) 294 (M+1).

EXAMPLE 96 7,7-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one Step 1: 1-Cyano 7,7-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

In the same way as described in Example 37, Step 1, using 4,4-dimethylcyclohexan-1,3-dione the title compound (0.2 g, 5%) was isolated as a colourless solid. ¹H NMR (250 MHz, CDCl₃) δ 1.55 (6H, s), 1.95 (2H, t, J=6.4 Hz), 2.60 (3H, s), 2.63 (2H, t, J=6.4 Hz).

Step 2: 7,7-Dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo [c]thiophene-1-thiocarboxamide

In the same way as described in Example 6, Step 2, using 1-cyano 7,7-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (170 mg, 61%) was isolated as a yellow solid. ¹H NMR (250 MHz, CDCl₃) δ 1.56 (6H, s), 1.89 (2H, t, J=6.8 Hz), 2.56 (3H, s), 2.61 (2H, t, J=6.8 Hz), 6.98 (1H, br s), 7.70 (1H, br s). MS (ES⁺) 286 (M+1).

Step 3: 7,7-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

In the same way as described in Example 6, Step 3, using 7,7-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo [c]thiophene-1-thiocarboxamide, the title compound (90 mg, 50%) was isolated as a colourless solid. mp 188-190° C. Found: C, 52.56; H, 4.85; N, 4.28%. C₁₄H₁₅NOS₃.0.5 (H₂O) requires: C, 52.80; H, 5.06; N, 4.40%. ¹H NMR (360 MHz, CDCl₃) δ 1.38 (6H, s), 1.89 (2H, t, J=6.5 Hz), 2.58 (3H, s), 2.63 (2H, t, J=6.5 Hz), 7.45 (1H, d, J=3.4 Hz), 7.89 (1H, d, J=3.4 Hz). MS (ES³⁰) 310 (M+1).

The following process was used to prepare Examples 97-105.

To a suspension of 6,6-dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one (50 mg, 0.16 mmol) in butanol (1mL) was added the appropriate amine (3.25 mmol). The mixture was heated at 100° C. for 24 h. The mixture was then diluted with MeOH:H₂O (1:1) and poured onto a C-18 Bond Elut cartridge (prewashed with MeOH followed by H₂O). The cartridge was eluted with MeOH:H₂O (10 mL) (1:1→1:0) and the product fractions evaporated. The residue was triturated with Et₂O to give the appropriate amino compound as a solid.

EXAMPLE 97 3-(Benzylamino)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 204-206° C. Found: C, 67.74; H, 5.92; N, 11.45%. C₂₀H₂₁N₃OS.0.25 (H₂O) requires: C, 67.48; H, 6.09; N, 11.80%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.99 (6H, s), 2.26 (2H, s), 2.68 (2H, s), 4.50 (2H, d, J=6.1 Hz), 6.34 (1H, br s), 7.24-7.40 (5H, m), 7.74 (1H, br s), 9.08-9.14 (1H, br m), 12.73 (1H, br s). MS (ES⁺) 352 (M+1).

EXAMPLE 98 6,6-Dimethyl-3-((furan-2-ylmethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 204-206° C. Found: C, 62.54; H, 5.36; N, 11.69%. C₁₈H₁₉N₂O₂S.0.35 (H₂O) requires: C, 62.17; H, 5.71; N, 12.08%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.98 (6H, s), 2.25 (2H, s), 2.68 (2H, s), 4.50 (2H, d, J=6.1 Hz), 6.36 (1H, br s), 6.40-6.45 (2H, m), 7.63 (1H, s), 7.76 (1H, br s), 8.90-8.95 (1h, br m), 12.76 (1H, br s). MS (ES⁺) 342 (M+1).

EXAMPLE 99 6,6-Dimethyl-3-((2-methylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 208-210° C. Found: C, 63.78; H, 7.21; N, 12.85%. C₁₇H₂₃N₃OS.0.2 (H₂O) requires: C, 63.60; H, 7.35; N, 13.09%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.94 (6H, d, J=6.7 Hz), 0.99 (6H, s), 1.92-2.02 (1H, m), 2.24 (2H, s), 2.68 (2H, s), 3.10 (2H, t, J=6.5 Hz), 6.37 (1H, br s), 7.76 (1H, br s), 8.72-8.78 (1H, br m), 12.76 (1H, br s). MS (ES⁺) 318 (M+1).

EXAMPLE 100 6,6-Dimethyl-3-(propylamino)-1-(pyrazol3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophen-4-one

mp 171-173° C.

¹H NMR (360 MHz, d₆-DMSO) δ 0.93 (3 H, t, J=7.4 Hz), 0.99 (6 H, s) 1.60-1.70 (2 H, m), 2.24 (2 H, s), 2.68 (2 H, s), 3.19-3.26 (2 H, m), 6.36 (1 H, br s), 7.76 (1 H, br s), 8.64-8.70 (1 H, br m), 12.76 (1 H, br s). MS (ES⁺) 304 (M+1).

EXAMPLE 101 6,6-Dimethyl-3-((3-imidazol-1-ylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 85° C. Found: C, 59.49; H, 6.53; N, 18.45%. C₁₉H₂₃N₅OS.0.7 (H₂O) requires: C, 59.72; H, 6.44; N, 18.33%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.99 (6 H, s), 2.06-2.16 (2 H, m), 2.24 (2 H, s), 2.68 (2 H, s), 3.18-3.26 (2 H, m), 4.05 (2 H, t, J=7.0 Hz), 6.36 (1 H, br s), 6.90 (1 H, s), 7.20 (1 H, s), 7.64 (1 H, s), 7.75 (1 H, br s), 8.62-8.68 (1 H, br m), 12.77 (1 H, br s). MS (ES⁺) 370 (M+1).

EXAMPLE 102 6,6-Dimethyl-3-((2-methoxyethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 171-173° C. Found: C, 59.19; H, 6.60; N, 12.49%. C₁₆H₂₁N₃OS.0.4 (H₂O) requires: C, 58.84; H, 6.73; N, 12.86%

¹H NMR (360 MHz, d₆-DMSO) δ 0.99 (6 H, s) 2.24 (2 H, m), 2.69 (2 H, s), 3.30 (3 H, m), 3.38-3.44 (2 H, m), 3.57 (2 H, t, J=5.3 Hz), 6.37 (1 H, br s), 7.76 (1 H, br s), 8.64-8.68 (1 H, br m), 12.77 (1 H, br s), MS (ES⁺) 320 (M+1).

EXAMPLE 103 3-Cyclopropylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 232-235° C. Found: C, 62.35; H, 6.24; N, 13.20%. C₁₆H₁₉N₃OS.0.45 (H₂O) requires: C, 62.09; H, 6.48; N, 13.58%.

¹H NMR (360 MHz, d₆-DMSO) δ 0.68-0.72 (2 H, m), 0.78-0.84 (2 H, m), 0.98 (6 H, s), 2.23 (2 H, s), 2.64-2.72 (3 H, m), 6.38 (1 H, br s), 7.76 (1 H, br s), 8.54 (1 H, br s), 12.77 (1 H, br s). MS (ES⁺) 302 (M+1).

EXAMPLE 104 6,6-Dimethyl-3-((pyrid-2-yl)methylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 210-213° C. found: C, 62.98; H, 5.49; N, 15.45%. C₁₉H₂₀N₄OS.0.5 (H₂O) requires: C, 63.13; H, 5.86, N, 15.50%.

¹H NMR (360 MHz, d₆-DMSO) δ 1.00 (6 H, s), 2.27 (2 H, s), 2.70 (2 H, s), 4.60 (2 H, d, J=5.8 Hz), 6.35 (1 H, s), 7.30-7.34 (1 H, m), 7.39-7.42 (1 H, m), 7.75 (1 H, br s), 7.78-7.83 (1 H, m), 8.56-8.60 (1 H, m), 9.26-9.32 (1 H, br m), 12.75 (1 H, br s), MS (ES⁺) 353 (M+1).

EXAMPLE 105 6,6-Dimethyl-3-([3-(4-methylpiperazin-1-yl)propyl]amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

mp 160-163° C. Found: C, 62.29; H, 8.14; N, 17.26%. C₂₁H₃₁N₅OS.0.25 (H₂O) requires: C, 62.11; H, 7.82; N, 17.25%

¹H NMR (360 MHz, d₆-DMSO) δ 0.98 (6 H, s) 1.74-1.82 (2 H, m), 2.15 (3 H, s), 2.23 (2 H, s), 2.28-2.40 (10 H, m), 2.68 (2 H, s), 3.26-3.32 (2 H, m), 6.36 (1 H, br s), 7.74 (1 H, br s), 8.70-8.76 (1 H, br s), 12.76 (1 H, br s). MS (ES⁺) 402 (M+1).

EXAMPLE 106 6,6-Dimethyl-3-methylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using methylamine, the title compound (92 mg, 89%) was isolated as an orange solid. mp 240-243° C. Found: C, 59.88; H, 6.22; N, 14.67%. C₁₄H₁₇N₃OS .0.3(H₂O) requires: C, 59.89; H, 6.32; N, 14.97%. ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6 H, s), 2.32 (2 H, s), 2.72 (2 H, s), 3.06 (3 H, d, J=5.2 Hz), 6.41 (1 H, br s), 7.60 (1 H, d, J=2.3 Hz). 8.58 (1 H, br s). MS (ES⁺) 276 (M+1).

EXAMPLE 107 6,6-Dimethyl-3-isopropylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using isopropylamine, the title compound (57 mg, 58%) was isolated as an orange solid. mp 215-218° C. Found: C, 63.09; H, 6.67; N, 13.65% C₁₆H₂₁N₃OS requires: C, 63.34; H, 6.98; N, 13.85%. ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6 H, s). 1.35 (6 H, d, J=6.3 Hz), 2.32 (2 H, s), 2.71 (2 H, s), 3.50-3.60 (1 H, m), 6.40 (1 H, d, J=2.2 Hz), 7.60 (1 H, d, J=2.4 Hz), 8.64-8.70 (1 H, br m). MS (ES⁺) 304 (M+1).

EXAMPLE 108 6,6-Dimethyl-3-ethylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using ethylamine, the title compound (66 mg, 70%) was isolated as a pale yellow solid. mp 237-240° C. Found: C, 61.16; H, 6.46; N, 14.02%. C₁₅H₁₉N₃OS .0.3(H₂O) requires: C, 61.11; H, 6.70; N, 14.25%. ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6 H, s), 1.36 (3 H, t, J=7.2 Hz), 2.32 (2 H, s), 2.72 (2 H, s), 3.30-3.38 (2 H, m), 6.41 (1 H, br s), 7.59 (1 H, br s), 8.58-8.66 (1 H, br m). MS (ES⁺) 290 (M+1).

EXAMPLE 109 6,6-Dimethyl-3-((2-hydroxyethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using ethanolamine, the title compound (57 mg, 58%) was isolated as a pale yellow solid. mp 227-230° C. Found: C, 58.18; H, 6.20; N, 13.24%. C₁₅H₁₉N₃OS .0.25(H₂O) requires: C, 58.14; H, 6.34; N, 13.56%. ¹H NMR (360 MHz, d₆-DMSO) δ 0.99 (6 H, s), 2.24 (2 H, s), 2.68 (2 H, s), 3.28-3.34 (2 H, m), 3.60-3.65 (2 H, m), 6.36 (1 H, d, J=2.2 Hz), 7.74 (1 H, d, J=2.3 Hz), 8.66-8.76 (1 H, m). MS (ES⁺) 306 (M+1).

EXAMPLE 110 3-Cyclobutylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using cyclobutylamine, the title compound (57 mg, 56%) was isolated as a pale yellow solid. mp 207-209° C. Found: C, 62.90; H, 6.42; N, 12.70%. C₁₇H₂₁N₃OS .0.45(H₂O) requires: C, 63.11; H, 6.82; N, 12.99%. ¹H NMR (360 MHz, CDCl₃) δ 1.05 (6 H, s), 1.76-1.96 (2 H, m), 2.02-2.26 (2 H, m), 2.32 (2 H, s), 2.44-2.54 (2 H, m), 2.71 (2 H, s), 3.86-2.96 (1 H, m), 6.40 (1 H, d, J=2.3 Hz), 7.62 (1 H, d, J=2.3 Hz). MS (ES⁺) 316 (M+1).

EXAMPLE 111 3-(Azetidin-1-yl)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 50 using zaetidine, the title compound (62 mg, 63%) was isolated as a yellow solid. mp 263-265° C. Found: C, 63.47; H, 6.35; N, 13.42%. C₁₆H₁₉N₃OS .0.15(H₂O) requires: C, 63.19; H, 6.40; N, 13.82%. ¹H NMR (360 MHz, CDCl₃) δ 1.04 (6 H, s), 2.31 (2 H, s), 2.36-2.45 (2 H, m), 2.74 (2 H, br s), 4.16-4.32 (4 H, m), 6.41 (1 H, br s), 7.62 (1 H, d, J=2.2 Hz). MS (ES⁺) 302 (M+1).

EXAMPLE 112 6,6-Dimethyl-3-isopropoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 24 using sodium isopropoxide in isopropanol and 6,6-dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (40 mg, 43%) was isolated as a yellow solid. mp 196-198° C. Found: C, 61.64; H, 6.44; N, 8.81%; C₁₆H₂₀N₂O₂S .0.4(H₂O) requires: C, 61.67; H, 6.73; N, 8.99%. ¹H NMR (360 MHz, CDCl₃) δ 1.06 (6 H, s), 1.51 (6 H, d, J=6.1 Hz), 2.36 (2 H, s), 2.80 (2 H, s), 4.54-4.62 (1 H, m), 6.45 (1 H, br s), 7.62 (1 H, d, J=2.3 Hz). MS (ES⁺) 305 (M+1).

EXAMPLE 113 3-Methylthio-1-(pyrid-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 33 using 1-bromo-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 3-pyridyl boronic acid, the title compound (62 mg, 62%) was obtained as a pale yellow solid. mp 130-132° C. Found: C, 61.26; H, 4.49; N, 4.85%. C₁₄H₁₃NOS₂ requires: C, 61.06; H, 4.76; N, 5.09% ¹H NMR (360 MHz, CDCl₃) δ 2.00-2.08 (2 H, m), 2.56-2.62 (2 H, m), 2.63 (3 H, s), 2.88-2.94 (2 H, m), 7.36-7.40 (1 H, m), 7.72-7.76 (1 H, m), 8.54-8.76 (2 H, br m). MS (ES⁺) 276 (M+1).

EXAMPLE 114 3-Methylthio-1-(pyrid-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as in Example 33 using 1-bromo-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one and 4-pyridyl boronic acid, the title compound (24 mg, 24%) was obtained as a yellow solid. mp 112-114° C. Found: C, 60.08; H, 4.35; N, 5.16%. C₁₄H₁₃NOS₂ .0.15(H₂O) requires: C, 60.47; H, 48.82; N, 5.04%. MS (ES⁺) 276 (M+1).

EXAMPLE 115 6,6-Dimethyl-3-methylthio-1-(2-methyl-1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid hydrazide

To a suspension of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid methyl ester (0.5 g, 1.8 mmol) in MeOH (10 mL) was added hydrzine monohydrate (0.51 mL, 10.5 mmol). This mixture was heated at reflux for 5 h. The solvent was evaporated and the residue triturated with ether to give the title compound (0.40 g, 80%) as a bright yellow solid. mp 225-228° C. Found: C, 48.26; H, 5.71; N, 9.34%; C₁₂H₁₆N₂O₂S₂ .0.75(H₂O) requires: C, 48.38; H, 5.92; N, 9.40%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6 H, s), 2.42 (2 H, s), 2.61 (3 H, s), 2.96 (2 H, s), 6.89 (1 H, br s). MS (ES⁺) 285 (M+1).

Step 2: 6,6-Dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid N′-acetyl hydrazide

To a suspension of the hydrazide (0.1 g, 0.35 mmol) in anhydrous DCM (4 mL) was added acetic anhydride (1 mL). The mixture was stirred at room temperature for 30 min. The solvent was evaporated and the residue azeotroped with toluene (2×10 mL). The residue was chromatographed on silica gel, eluting with DCM:MeOH (19:1) to give the title compound (90 mg, 78%) as a pale yellow solid. mp. 133-135° C. Found: C, 51.20; H, 5.37; N, 8.34%. C₁₄H₁₈N₂O₃S₂ requires: C, 51.51; H, 5.56; N, 8.58%. ¹H NMR (6 H, s), 2.14 (3 H, s), 2.41 (2 H, s), 2.60 (3 H, s), 2.99 (2 H, s), 8.44-8.52 (2 H, m). MS (ES⁺) 327 (M+1).

Step 3: 6,6-Dimethyl-3-methylthio-1-(2-methyl-1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

To a suspension of the hydrazide (62 mg, 0.2 mmol) in dry toluene (5 mL) was added thionyl chloride (19 μL, 0.26 mmol) and triethylamine (44 μL, 0.23 mmol). This mixture was heated at 90° C. for 1 h. The solvent was evaporated and the residue chromatographed on silica using EtOAC:DCM (1:9) as the eluent. The fractions containing the desired product were combined and evaporated and the residue triturated with ether. The title compound (39 mg, 64%) was isolated as a pale yellow solid. mp 186-188° C. Found: C, 53.96; H, 4.76; N, 8.95%. C₁₄H₁₆N₂O₂S₂ .0.1(H₂O) requires: C, 54.20; H, 5.26; N, 9.03%. ¹H NMR (360 MHz, CDCl₃) δ 1.10 (6 H, s), 2.45 (2 H, s), 2.61 (3 H, s) 2.65 (3 H, s), 3.07 (2 H, s). MS (ES⁺) 309 (M+1).

EXAMPLE 116 6,6-Dimethyl-3-methylthio-1-(1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one Step 1: 6,6-Dimethyl-3-methylthio-1-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid N′-formyl hydrazide

A solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid hydrazide (0.1 g, 0.35 mmol) in formic acid (98%, 2 mL) was heated at reflux for 2 h. The solvent was evaporated and the residue azeotroped with toluene (2×10 mL). The residue was chromatographed on silica with DCM:MeOH (19:1→9:1). The fractions containing the desired product were combined and evaporated and the residue triturated with ether. The title compound (90 mg, 82%) was isolated as a yellow solid. mp 87-90° C. found: C, 49.33; H, 5.26; N, 8.37%. C₁₃H₁₆N₂O₃S₂ 0.4(H₂O) .0.15(Et₂O) requires: C, 49.39; H, 5.58; N, 8.47%. ¹H NMR (360 MHz, CDCl₃) δ 1.07 (6 H, s), 2.42 (2 H, s), 2.60 (3 H, s), 3.00 (2 H, s), 8.23 (1 H, s), 8.44-8.50 (1 H, m), 8.54-8.60 (1 H, m). MS (ES⁺) 313 (M+1).

Step 2: 6,6-Dimethyl-3-methylthio-1-(1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one

In the same way as Example 115, Step 3, the title compound (27 mg, 41%) was obtained as a yellow solid. mp 185-189° C. Found: C, 51.86; H, 4.65; N, 8.84%. C₁₃H₁₄N₂O₂S₂ 0.5(H₂O) requires: C, 51.46; H, 4.98; N, 9.23% ¹H NMR (360 MHz, CDCl₃) δ 1.11 (6 H, s), 2.46 (2 H, s), 2.66 (3 H, s), 3.11 (2 H, s), 8.41 (1 H, s). MS (ES⁺) 295 (M+1).

The following compounds of formula I in which q is 1 and R² and R³ are 6,6-dimethyl also form part of the present invention and can be made by the processes disclosed herein. They all have K_(i) value of less than 100 nM as measured by the aforementioned test method.

A B 1. methylthio (2-methylthio)pyrimidin-4-yl 2. methylthio 3-(N,N-dimethyl)propenonyl 3. methylthio (4-bromo)pyrazol-3-yl 4. methylthio [N-(4-chlorophenyl)aminocarbonyl]pyrazol-3-yl 5. methylthio pyrazol-3-yl 6. methylthio (4-ethoxycarbonyl)thiazol-2-yl 7. methylthio [(N-phenyl)aminocarbonyl]pyrazol-3-yl 8. methylthio (1-methylcarbonyl)pyrazol-3-yl 9. 4-chloro- 3-(N,N-dimethyl)propenonyl benzylthio 10. methylthio 2-[N-(4-chlorophenyl)aminocarbonylmethylthio] pyrimidin-4-yl 

What is claimed is:
 1. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

where A is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, arylC₁₋₆alkyl, aryl, S(O)_(p)R¹, OR¹ or NR¹R¹⁴; B is a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from: C₁₋₆alkyl; C₁₋₆haloalkyl; halogen; S(O)_(r)R⁴; COR⁵; and aryl or aryl C₁₋₆alkyl wherein the aryl ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano; R¹ is hydrogen; C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkenyl each of which is optionally substituted by amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl, one, two or three hydroxy groups, one, two or three halogen atoms or a four, five or six-membered saturated heterocyclic ring containing a nitrogen atom and optionally either an oxygen atom or a further nitrogen atom which ring is optionally substituted by C₁₋₄alkyl on the further nitrogen atom; aryl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl or aryl C₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro, cyano, C₁₋₆alkylcarbonylamino, hydroxy or C₁₋₆alkoxy; or a five-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by halogen, C₁₋₆alkoxy, C₁₋₆alkylthio, aryl, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; R² and R³ are independently hydrogen or C₁₋₆alkyl or together with the carbon atom to which they are attached form a C₃₋₈cycloalkyl group; R⁴ is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl or CH₂(CO)_(m)NR⁸R⁹; R⁵ is NR⁶R⁷, C₁₋₆alkyl or C₁₋₆alkoxy; R⁶ is independently as defined for R⁴; R⁷ is aryl optionally substituted by halogen, nitro or cyano; R⁸ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₂₋₆alkenyl, C₂₋₆alkynyl; arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro or cyano; thiophene or pyridine; R⁹ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano; R¹⁴ is hydrogen or C₁₋₆alkyl; m is zero or 1; p is zero, 1 or 2; q is 1 or 2; and r is 0, 1 or 2; and a pharmaceutically acceptable excipient.
 2. A composition according to claim 1 in which: A is SR¹; B is a nitrogen containing aromatic ring which is 5-membered and contains 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or is 6-membered and contains 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by C₁₋₆alkyl, halogen, SR⁴, COR⁵ or benzyl optionally substituted by one or two substituents independently chosen from halogen, nitro and cyano; R¹ is C₁₋₆alkyl, C₁₋₄alkenyl, or C₃₋₆cycloalkyl each of which is optionally substituted by di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylaminocarbonyl, one or two hydroxy groups or three fluorine atoms; phenyl or phenylC₁₋₄alkyl optionally substituted on the phenyl ring by chlorine, fluorine, C₁₋₄alkoxy or C₁₋₄alkylcarbonylamino; or a pyridine, thiophene, furan, pyrimidine, thiazole, imidazole, triazole or thiadiazole, each of which is unsubstituted or substituted by C₁₋₄alkyl, phenyl, fluorine or C₁₋₄alkylthio; R² and R³ are independently chosen from hydrogen and methyl; R⁴ is hydrogen, methyl or CH₂CONR⁸R⁹; R⁵ is methyl, methoxy, ethoxy or NR⁶R⁷; R⁶ is hydrogen or C₁₋₄alkyl; R⁷ is phenyl unsubstituted or substituted by halogen, nitro or cyano; R⁸ is hydrogen or C₁₋₆alkyl; R⁹ is C₁₋₆alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen or nitro; R¹⁴ is hydrogen or C₁₋₄alkyl; p is zero; and q is
 1. 3. A composition according to claim 1 in which the compound of formula I is 6,6-Dimethyl-1-(2-methyltetrazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-ethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(2-propyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(1-methanesulphonylpyrazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(2-methylprop-1-yl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-propyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-phenyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one.
 4. A compound of formula I or a pharmaceutically acceptable salt thereof

wherein A is C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, arylC₁₋₆alkyl, aryl, S(O)_(p)R¹, OR¹ or NR¹R¹⁴; B is a 5-membered ring having one or two unsaturations containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a 6-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by one or more substituents independently chosen from: C₁₋₆alkyl; C₁₋₆haloalkyl; halogen; S(O)_(r)R⁴; COR⁵; and aryl or aryl C₁₋₆alkyl wherein the aryl ring is optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano; R¹ is hydrogen; C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl or C₃₋₆cycloalkenyl each of which is optionally substituted by amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆alkoxy, C₁₋₆alkylaminocarbonyl, one, two or three hydroxy groups, one, two or three halogen atoms or a four, five or six-membered saturated heterocyclic ring containing a nitrogen atom and optionally either an oxygen atom or a further nitrogen atom which ring is optionally substituted by C₁₋₄alkyl on the further nitrogen atom; aryl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro, cyano, C₁₋₆alkylcarbonylamino, hydroxy or C₁₋₆alkoxy; or a five-membered aromatic ring containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or a six-membered aromatic ring containing 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by halogen, C₁₋₆alkoxy, C₁₋₆alkylthio, aryl, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl; R² and R³ are independently hydrogen or C₁₋₆alkyl or together with the carbon atom to which they are attached form a C₃₋₈cycloalkyl group; R⁴ is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl or CH₂(CO)_(m)NR⁸R⁹; R⁵ is NR⁶R⁷, C₁₋₆alkyl or C₁₋₆alkoxy; R⁶ is independently as defined for R⁴; R⁷ is aryl optionally substituted by halogen, nitro or cyano; R⁸ is hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkenyl, C₂₋₆alkenyl, C₂₋₆alkynyl; arylC₁₋₆alkyl, arylC₂₋₆alkenyl or arylC₂₋₆alkynyl optionally substituted on the aryl ring by halogen, nitro or cyano; thiophene or pyridine; R⁹ is C₁₋₆alkyl; C₂₋₆alkenyl; C₂₋₆alkynyl; or phenyl optionally substituted by one, two or three substituents independently chosen from halogen, CF₃, OCH₃, nitro and cyano; R¹⁴ is hydrogen or C₁₋₆alkyl; m is zero or 1; p is zero, 1 or 2; q is 1 or 2; and r is 0, 1 or
 2. 5. A method of treatment of a condition associated with GABA_(A) receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 4 wherein A is SR¹; B is a nitrogen containing aromatic ring which is 5-membered and contains 1, 2, 3 or 4 heteroatoms chosen from O, N and S provided that not more than one heteroatom is other than N, or is 6-membered and contains 1, 2, 3 or 4 nitrogen atoms, which ring is optionally substituted by C₁₋₆alkyl, halogen, SR⁴, COR⁵ or benzyl optionally substituted by one or two substituents independently chosen from halogen, nitro and cyano; R¹ is C₁₋₆alkyl, C₁₋₄alkenyl, or C₃₋₆cycloalkyl each of which is optionally substituted by di(C₁₋₄alkyl)amino, C₁₋₄alkoxy, C₁₋₄alkylaminocarbonyl, one or two hydroxy groups or three fluorine atoms; phenyl or phenylC₁₋₄alkyl optionally substituted on the phenyl ring by chlorine, fluorine, C₁₋₄alkoxy or C₁₋₄alkylcarbonylamino; or a pyridine, thiophene, furan, pyrimidine, thiazole, imidazole, triazole or thiadiazole, each of which is unsubstituted or substituted by C₁₋₄alkyl, phenyl, fluorine or C₁₋₄alkylthio; R² and R³ are independently chosen from hydrogen and methyl; R⁴ is hydrogen, methyl or CH₂CONR⁸R⁹; R⁵ is methyl, methoxy, ethoxy or NR⁶R⁷; R⁶ is hydrogen or C₁₋₄alkyl; R⁷ is phenyl unsubstituted or substituted by halogen, nitro or cyano; R⁸ is hydrogen or C₁₋₆alkyl; R⁹ is C₁₋₆alkyl or phenyl optionally substituted by one or two substituents independently chosen from halogen or nitro; R¹⁴ is hydrogen or C₁₋₄alkyl; p is zero; and q is
 1. 7. The compound of claim 4 in which the compound of formula I is 6,6-Dimethyl-1-(2-methyltetrazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methanesulphinyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-ethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(2-propyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(1-methanesulphonylpyrazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(2-methylprop-1-yl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-propyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-phenyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclohexyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclobutyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-(But-3-enyl)-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclopropyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(2-methylprop-1-enyl)-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methanesulphonyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 1-(Thiazol-2-yl)-3,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Benzyl-6,6-dimethyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-((1-phenylsulphonyl)pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropylthio-1-(2-methyltetrazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 1-(1-Acetylpyrazol-3-yl)-6,6-dimethyl-3-methanesulphinyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-[(1,1-dimethylethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(4-methyl-1,2,4-triazol-3- yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-((4-ethoxycarbonyl)thiazol-2yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-((4-trifluoromethyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-dimethylamino-1-((4-ethoxycarbonyl)thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 1-((4-Acetyl)thiazol-2-yl)-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-((4-methyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(pyrazol-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(pyrrol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-hydroxyethyl)thio)-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-1-(thiazol-2-yl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[c]thiophen; 6,6-Dimethyl-3-methylthio-1-(3-methyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(4-benzyl-1,2,4-triazol-3-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(1-methyl-1,2,4-triazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(oxazolidin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-1-(oxazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(pyrazin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(pyrimidin-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(imidazolin-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-6,6-spirocyclohexyl-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(3-(N-methylaminocarbonyl)thiazol-2-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(thiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-tert-butylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclobutoxy-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-[(3-ethoxycarbonyl)isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-phenoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-pentylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Butylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-[(3-Chloropropyl)thio]-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-phenylethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-propylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-methylbutyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((2,2,2-trifluoroethyl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-((4-Chlorophenyl)thio)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((3-fluorophenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-((4-Acetylaminophenyl)thio)-6,6-dimethyl-1-pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((4-methoxyphenyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((1-methylimidazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((thiophen-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((imidazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((4-phenylthiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((1,2,4-triazol-3-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((5-methyl-1,3,4-thiadiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((4-methyl-1,2,4-triazol-3-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((5-methylthio-1,3,4-thiadiazol-2-yl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Benzylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclopentylthio-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-hexylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((furan-2-ylmethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-hydroxy-1-methylpropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2,3-dihydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-hydroxypropyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(((N-methylaminocarbonyl)methyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-4-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrimidin-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((thiazol-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(prop-2-enylthio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(pyrazol-3-yl)-3-((pyrid-2-yl)thio)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-ethylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-phenylthio-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((N,N-dimethyl-2-aminoethyl)thio)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-[(2-hydroxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-[(2-hydroxypropyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-[(2-methoxyethyl)thio]-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-1-(isoxazol-5-yl)-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 7,7-Dimethyl-3-methylthio-1-(thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-(Benzylamino)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((furan-2-ylmethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-methylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-(propylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((3-imidazol-1-ylpropyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-methoxyethyl)amino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclopropylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((pyrid-2-yl)methylamino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-([3-(4-methylpiperazin-1-yl)propyl]amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-ethylamino-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-((2-hydroxyethyl)amino)-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Cyclobutylamino-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-(Azetidin-1-yl)-6,6-dimethyl-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-isopropoxy-1-(pyrazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-1-(pyrid-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 3-Methylthio-1-(pyrid-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; 6,6-Dimethyl-3-methylthio-1-(2-methyl-1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; or 6,6-Dimethyl-3-methylthio-1-(1,3,4-oxadiazol-5-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one; or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 4 wherein q is 1; R² and R³ are 6,6-dimethyl; and A and B are chosen from the following pairings: A B
 1. methylthio (2-methylthio)pyrimidin-4-yl
 3. methylthio (4-bromo)pyrazol-3-yl
 4. methylthio {N-(4-chlorophenyl)aminocarbonyl}pyrazol-3-yl
 5. methylthio pyrazol-3-yl
 6. methylthio (4-ethoxycarbonyl)thiazol-2-yl
 7. methylthio {(N-phenyl)aminocarbonyl}pyrazol-3-yl
 8. methylthio (1-methylcarbonyl)pyrazol-3-yl
 10. methylthio 2-{N-(4-chlorophenyl)aminocarbonylmethylthio} pyrimidin-4-yl

or a pharmaceutically acceptable salt thereof.
 9. A method of treatment of a condition associated with GABA_(A) receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically effective amount of a compound of formula I as defined in claim 6 or a pharmaceutically acceptable salt thereof.
 10. A method of treatment of a condition associated with GABA_(A) receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically effective amount of a compound of formula I as defined in claim 7 or a pharmaceutically acceptable salt thereof.
 11. A method of treatment of a condition associated with GABA_(A) receptors containing the α5 subunit which comprises administering to a subject suffering from or prone to such a condition a therapeutically effective amount of a compound of formula I as defined in claim 8 or a pharmaceutically acceptable salt thereof.
 12. The method of claim 5 wherein the condition associated with GABA_(A) receptors containing the α5 subunit is Alzheimer's disease.
 13. The method of claim 9 wherein the condition associated with GABA_(A) receptors containing the α5 subunit is Alzheimer's disease.
 14. The method of claim 10 wherein the condition associated with GABA_(A) receptors containing the α5 subunit is Alzheimer's disease.
 15. The method of claim 11 wherein the condition associated with GABA_(A) receptors containing the α5 subunit is Alzheimer's disease. 